Abstract
Following myocardial ischemic injury, the most effective clinical intervention is timely restoration of blood perfusion to ischemic but viable myocardium to reduce irreversible myocardial necrosis, limit infarct size, and prevent cardiac insufficiency. However, reperfusion itself may exacerbate cell death and myocardial injury, a process commonly referred to as ischemia/reperfusion (I/R) injury, which primarily involves cardiomyocytes and cardiac microvascular endothelial cells (CMECs) and is characterized by myocardial stunning, microvascular damage (MVD), reperfusion arrhythmia, and lethal reperfusion injury. MVD caused by I/R has been a neglected problem compared to myocardial injury. Clinically, the incidence of microvascular angina and/or no-reflow due to ineffective coronary perfusion accounts for 5–50% in patients after acute revascularization. MVD limiting drug diffusion into injured myocardium, is strongly associated with the development of heart failure. CMECs account for > 60% of the cardiac cellular components, and their role in myocardial I/R injury cannot be ignored. There are many studies on microvascular obstruction, but few studies on microvascular leakage, which may be mainly due to the lack of corresponding detection methods. In this review, we summarize the clinical manifestations, related mechanisms of MVD during myocardial I/R, laboratory and clinical examination means, as well as the research progress on potential therapies for MVD in recent years. Better understanding the characteristics and risk factors of MVD in patients after hemodynamic reconstruction is of great significance for managing MVD, preventing heart failure and improving patient prognosis.
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References
Li Y, Schoufour J, Wang DD et al (2020) Healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: prospective cohort study. BMJ 368:l6669. https://doi.org/10.1136/bmj.l6669
Bhatnagar A (2017) Environmental determinants of cardiovascular disease. Circ Res 121(2):162–180. https://doi.org/10.1161/CIRCRESAHA.117.306458
Wang W, Hu M, Liu H et al (2021) Global Burden of Disease Study 2019 suggests that metabolic risk factors are the leading drivers of the burden of ischemic heart disease. Cell Metab 33(10):1943-1956e1942. https://doi.org/10.1016/j.cmet.2021.08.005
Balakumar P, Maung UK, Jagadeesh G (2016) Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res 113(Pt A):600–609. https://doi.org/10.1016/j.phrs.2016.09.040
Organization WH (2021) Cardiovascular diseases (CVDs). Retrieved from https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). Accessed 14 Feb 2023
Roth GA, Mensah GA, Johnson CO et al (2020) Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 Study. J Am Coll Cardiol 76(25):2982–3021. https://doi.org/10.1016/j.jacc.2020.11.010
Smit M, Coetzee AR, Lochner A (2020) The pathophysiology of myocardial ischemia and perioperative myocardial infarction. J Cardiothorac Vasc Anesth 34(9):2501–2512. https://doi.org/10.1053/j.jvca.2019.10.005
Mozaffarian D, Benjamin EJ, Go AS et al (2015) Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation 131(4):e29-322. https://doi.org/10.1161/CIR.0000000000000152
Crea F, Camici PG, Bairey Merz CN (2014) Coronary microvascular dysfunction: an update. Eur Heart J 35(17):1101–1111. https://doi.org/10.1093/eurheartj/eht513
Chang X, Lochner A, Wang HH et al (2021) Coronary microvascular injury in myocardial infarction: perception and knowledge for mitochondrial quality control. Theranostics 11(14):6766–6785. https://doi.org/10.7150/thno.60143
Kleinbongard P, Heusch G (2022) A fresh look at coronary microembolization. Nat Rev Cardiol 19(4):265–280. https://doi.org/10.1038/s41569-021-00632-2
Zhong J, Ouyang H, Sun M et al (2019) Tanshinone IIA attenuates cardiac microvascular ischemia-reperfusion injury via regulating the SIRT1-PGC1alpha-mitochondrial apoptosis pathway. Cell Stress Chaperones 24(5):991–1003. https://doi.org/10.1007/s12192-019-01027-6
Khuddus MA, Pepine CJ, Handberg EM et al (2010) An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: a substudy from the National Heart, Lung and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). J Interv Cardiol 23(6):511–519. https://doi.org/10.1111/j.1540-8183.2010.00598.x
Reynolds HR, Diaz A, Cyr DD et al (2023) Ischemia with nonobstructive coronary arteries: insights from the ISCHEMIA Trial. JACC Cardiovasc Imaging 16(1):63–74. https://doi.org/10.1016/j.jcmg.2022.06.015
Camici PG, Crea F (2007) Coronary microvascular dysfunction. N Engl J Med 356(8):830–840. https://doi.org/10.1056/NEJMra061889
Heusch G (2016) The coronary circulation as a target of cardioprotection. Circ Res 118(10):1643–1658. https://doi.org/10.1161/CIRCRESAHA.116.308640
Lambert L, Brown K, Segal E et al (2010) Association between timeliness of reperfusion therapy and clinical outcomes in ST-elevation myocardial infarction. JAMA 303(21):2148–2155. https://doi.org/10.1001/jama.2010.712
He J, Bellenger NG, Ludman AJ et al (2022) Treatment of myocardial ischaemia-reperfusion injury in patients with ST-segment elevation myocardial infarction: promise, disappointment, and hope. Rev Cardiovasc Med 23(1):23. https://doi.org/10.31083/j.rcm2301023
Wu S, Chang G, Gao L et al (2018) Trimetazidine protects against myocardial ischemia/reperfusion injury by inhibiting excessive autophagy. J Mol Med (Berl) 96(8):791–806. https://doi.org/10.1007/s00109-018-1664-3
Davidson SM, Ferdinandy P, Andreadou I et al (2019) Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. J Am Coll Cardiol 73(1):89–99. https://doi.org/10.1016/j.jacc.2018.09.086
Yang CF (2018) Clinical manifestations and basic mechanisms of myocardial ischemia/reperfusion injury. Ci Ji Yi Xue Za Zhi 30(4):209–215. https://doi.org/10.4103/tcmj.tcmj_33_18
Wu E, Ortiz JT, Tejedor P et al (2008) Infarct size by contrast enhanced cardiac magnetic resonance is a stronger predictor of outcomes than left ventricular ejection fraction or end-systolic volume index: prospective cohort study. Heart 94(6):730–736. https://doi.org/10.1136/hrt.2007.122622
Majidi M, Kosinski AS, Al-Khatib SM et al (2009) Reperfusion ventricular arrhythmia “bursts” predict larger infarct size despite TIMI 3 flow restoration with primary angioplasty for anterior ST-elevation myocardial infarction. Eur Heart J 30(7):757–764. https://doi.org/10.1093/eurheartj/ehp005
Saia F, Grigioni F, Marzocchi A et al (2010) Management of acute left ventricular dysfunction after primary percutaneous coronary intervention for ST elevation acute myocardial infarction. Am Heart J 160(6 Suppl):S16-21. https://doi.org/10.1016/j.ahj.2010.10.011
Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357(11):1121–1135. https://doi.org/10.1056/NEJMra071667
Zou R, Shi W, Qiu J et al (2022) Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis. Cardiovasc Diabetol 21(1):106. https://doi.org/10.1186/s12933-022-01532-6
Wang J, Toan S, Zhou H (2020) New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury. Angiogenesis 23(3):299–314. https://doi.org/10.1007/s10456-020-09720-2
Wang J, Toan S, Zhou H (2020) Mitochondrial quality control in cardiac microvascular ischemia-reperfusion injury: new insights into the mechanisms and therapeutic potentials. Pharmacol Res 156:104771. https://doi.org/10.1016/j.phrs.2020.104771
Wu D, Ji H, Du W et al (2022) Mitophagy alleviates ischemia/reperfusion-induced microvascular damage through improving mitochondrial quality control. Bioengineered 13(2):3596–3607. https://doi.org/10.1080/21655979.2022.2027065
Chia PY, Teo A, Yeo TW (2020) Overview of the assessment of endothelial function in humans. Front Med (Lausanne) 7:542567. https://doi.org/10.3389/fmed.2020.542567
Kloka JA, Friedrichson B, Wulfroth P et al (2023) Microvascular leakage as therapeutic target for ischemia and reperfusion injury. Cells. https://doi.org/10.3390/cells12101345
Pinto AR, Ilinykh A, Ivey MJ et al (2016) Revisiting cardiac cellular composition. Circ Res 118(3):400–409. https://doi.org/10.1161/CIRCRESAHA.115.307778
Bassenge E, Heusch G (1990) Endothelial and neuro-humoral control of coronary blood flow in health and disease. Rev Physiol Biochem Pharmacol 116:77–165. https://doi.org/10.1007/3540528806_4
Ibanez B, James S, Agewall S et al (2017) 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Rev Esp Cardiol (Engl Ed) 70(12):1082. https://doi.org/10.1016/j.rec.2017.11.010
Ibanez B, James S, Agewall S et al (2018) 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 39(2):119–177. https://doi.org/10.1093/eurheartj/ehx393
Annibali G, Scrocca I, Aranzulla TC et al (2022) “No-Reflow” phenomenon: a contemporary review. J Clin Med. https://doi.org/10.3390/jcm11082233
Cai C, Guo Z, Chang X et al (2022) Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKalpha1/ULK1/FUNDC1/mitophagy pathway. Redox Biol 52:102288. https://doi.org/10.1016/j.redox.2022.102288
Heusch G, Kleinbongard P, Bose D et al (2009) Coronary microembolization: from bedside to bench and back to bedside. Circulation 120(18):1822–1836. https://doi.org/10.1161/CIRCULATIONAHA.109.888784
Alidoosti M, Lotfi R, Lotfi-Tokaldany M et al (2018) Correlates of the "No-Reflow" or "Slow-Flow" phenomenon in patients undergoing primary percutaneous coronary intervention. J Tehran Heart Cent, 13(3), 108–114. https://www.ncbi.nlm.nih.gov/pubmed/30745923. Accessed 15 Aug 2023
Ambrosio G, Weisman HF, Mannisi JA et al (1989) Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation 80(6):1846–1861. https://doi.org/10.1161/01.cir.80.6.1846
Reffelmann T, Kloner RA (2002) Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit. Am J Physiol Heart Circ Physiol 283(3):H1099-1107. https://doi.org/10.1152/ajpheart.00270.2002
Harrison RW, Aggarwal A, Ou FS et al (2013) Incidence and outcomes of no-reflow phenomenon during percutaneous coronary intervention among patients with acute myocardial infarction. Am J Cardiol 111(2):178–184. https://doi.org/10.1016/j.amjcard.2012.09.015
Schwartz BG, Kloner RA (2012) Coronary no reflow. J Mol Cell Cardiol 52(4):873–882. https://doi.org/10.1016/j.yjmcc.2011.06.009
Ndrepepa G, Tiroch K, Fusaro M et al (2010) 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol 55(21):2383–2389. https://doi.org/10.1016/j.jacc.2009.12.054
Niccoli G, Montone RA, Ibanez B et al (2019) Optimized treatment of ST-elevation myocardial infarction. Circ Res 125(2):245–258. https://doi.org/10.1161/CIRCRESAHA.119.315344
van Kranenburg M, Magro M, Thiele H et al (2014) Prognostic value of microvascular obstruction and infarct size, as measured by CMR in STEMI patients. JACC Cardiovasc Imaging 7(9):930–939. https://doi.org/10.1016/j.jcmg.2014.05.010
Aggarwal P, Rekwal L, Sinha SK et al (2021) Predictors of no-reflow phenomenon following percutaneous coronary intervention for ST-segment elevation myocardial infarction. Ann Cardiol Angeiol (Paris) 70(3):136–142. https://doi.org/10.1016/j.ancard.2021.04.004
Ramadan R, Vromans E, Anang DC et al (2020) Connexin43 hemichannel targeting with TAT-Gap19 alleviates radiation-induced endothelial cell damage. Front Pharmacol 11:212. https://doi.org/10.3389/fphar.2020.00212
Wang L, Ge C, Zhang X (2022) Sufentanil ameliorates oxygen-glucose deprivation/reoxygenation-induced endothelial barrier dysfunction in HCMECs via the PI3K/Akt signaling pathway. Exp Ther Med 24(1):437. https://doi.org/10.3892/etm.2022.11364
Gao XM, Wu QZ, Kiriazis H et al (2017) Microvascular leakage in acute myocardial infarction: characterization by histology, biochemistry, and magnetic resonance imaging. Am J Physiol Heart Circ Physiol 312(5):H1068–H1075. https://doi.org/10.1152/ajpheart.00073.2017
Kloner RA, Ganote CE, Jennings RB (1974) The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 54(6):1496–1508. https://doi.org/10.1172/JCI107898
Heusch G (2019) Coronary microvascular obstruction: the new frontier in cardioprotection. Basic Res Cardiol 114(6):45. https://doi.org/10.1007/s00395-019-0756-8
Kang S, Yang Y (2007) Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction. Clin Invest Med 30(3):E133-145. https://doi.org/10.25011/cim.v30i3.1082
Erkol A, Oduncu V, Turan B et al (2014) The value of plasma D-dimer level on admission in predicting no-reflow after primary percutaneous coronary intervention and long-term prognosis in patients with acute ST segment elevation myocardial infarction. J Thromb Thrombolysis 38(3):339–347. https://doi.org/10.1007/s11239-013-1044-3
Grygier M, Araszkiewicz A, Lesiak M et al (2014) Intracoronary adenosine administered during aortocoronary vein graft interventions may reduce the incidence of no-reflow phenomenon. A pilot randomised trial. Kardiol Pol 72(2):126–133. https://doi.org/10.5603/KP.a2013.0213
Li J, Wu L, Tian X et al (2015) Intravascular ultrasound observation of the mechanism of no-reflow phenomenon in acute myocardial infarction. PLoS ONE 10(6):e0119223. https://doi.org/10.1371/journal.pone.0119223
Cenko E, Ricci B, Kedev S et al (2016) The no-reflow phenomenon in the young and in the elderly. Int J Cardiol 222:1122–1128. https://doi.org/10.1016/j.ijcard.2016.07.209
Chen WR, Tian F, Chen YD et al (2016) Effects of liraglutide on no-reflow in patients with acute ST-segment elevation myocardial infarction. Int J Cardiol 208:109–114. https://doi.org/10.1016/j.ijcard.2015.12.009
Durante A, Laricchia A, Benedetti G et al (2017) Identification of high-risk patients after ST-segment-elevation myocardial infarction: comparison between angiographic and magnetic resonance parameters. Circ Cardiovasc Imaging 10(6):e005841. https://doi.org/10.1161/CIRCIMAGING.116.005841
Liang T, Liu M, Wu C et al (2017) Risk factors for no-reflow phenomenon after percutaneous coronary intervention in patients with acute coronary syndrome. Rev Invest Clin 69(3):139–145. https://doi.org/10.24875/ric.17002190
Li H, Fu DG, Liu FY et al (2018) Evaluation of related factors, prediction and treatment drugs of no-reflow phenomenon in patients with acute ST-segment elevation myocardial infarction after direct PCI. Exp Ther Med 15(4):3940–3946. https://doi.org/10.3892/etm.2018.5900
Mahmoud AH, Taha NM, Baraka K et al (2019) Clinical and procedural predictors of suboptimal myocardial reperfusion in primary percutaneous coronary intervention. Int J Cardiol Heart Vasc 23:100357. https://doi.org/10.1016/j.ijcha.2019.100357
Yang L, Cong H, Lu Y et al (2020) Prediction of no-reflow phenomenon in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Medicine (Baltimore) 99(26):e20152. https://doi.org/10.1097/MD.0000000000020152
Rossington JA, Sol E, Masoura K et al (2020) No-reflow phenomenon and comparison to the normal-flow population postprimary percutaneous coronary intervention for ST elevation myocardial infarction: case-control study (NORM PPCI). Open Heart. https://doi.org/10.1136/openhrt-2019-001215
Sadeghian M, Mousavi SH, Aamaraee Z et al (2022) Administration of intracoronary adenosine before stenting for the prevention of no-reflow in patients with ST-elevation myocardial infarction. Scand Cardiovasc J 56(1):23–27. https://doi.org/10.1080/14017431.2022.2035807
d’Entremont MA, Alazzoni A, Dzavik V et al (2023) No-reflow after primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction: an angiographic core laboratory analysis of the TOTAL Trial. EuroIntervention 19(5):e394–e401. https://doi.org/10.4244/EIJ-D-23-00112
Eitel I, Wohrle J, Suenkel H et al (2013) Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the AIDA STEMI trial. J Am Coll Cardiol 61(13):1447–1454. https://doi.org/10.1016/j.jacc.2013.01.048
Hadamitzky M, Langhans B, Hausleiter J et al (2014) Prognostic value of late gadolinium enhancement in cardiovascular magnetic resonance imaging after acute ST-elevation myocardial infarction in comparison with single-photon emission tomography using Tc99m-Sestamibi. Eur Heart J Cardiovasc Imaging 15(2):216–225. https://doi.org/10.1093/ehjci/jet176
Kandler D, Lucke C, Grothoff M et al (2014) The relation between hypointense core, microvascular obstruction and intramyocardial haemorrhage in acute reperfused myocardial infarction assessed by cardiac magnetic resonance imaging. Eur Radiol 24(12):3277–3288. https://doi.org/10.1007/s00330-014-3318-3
Ding S, Li Z, Ge H et al (2015) Impact of early ST-segment changes on cardiac magnetic resonance-verified intramyocardial haemorrhage and microvascular obstruction in ST-elevation myocardial infarction patients. Medicine (Baltimore) 94(35):e1438. https://doi.org/10.1097/MD.0000000000001438
Kim EK, Hahn JY, Song YB et al (2015) Effect of ischemic postconditioning on myocardial salvage in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the POST randomized trial. Int J Cardiovasc Imaging 31(3):629–637. https://doi.org/10.1007/s10554-015-0589-y
Desch S, Stiermaier T, de Waha S et al (2016) Thrombus aspiration in patients with ST-segment elevation myocardial infarction presenting late after symptom onset. JACC Cardiovasc Interv 9(2):113–122. https://doi.org/10.1016/j.jcin.2015.09.010
Carrick D, Haig C, Ahmed N et al (2016) Myocardial Hemorrhage after acute reperfused ST-segment-elevation myocardial infarction: relation to microvascular obstruction and prognostic significance. Circ Cardiovasc Imaging 9(1):e004148. https://doi.org/10.1161/CIRCIMAGING.115.004148
Nazir SA, McCann GP, Greenwood JP et al (2016) Strategies to attenuate micro-vascular obstruction during P-PCI: the randomized reperfusion facilitated by local adjunctive therapy in ST-elevation myocardial infarction trial. Eur Heart J 37(24):1910–1919. https://doi.org/10.1093/eurheartj/ehw136
Kloner RA (2017) The importance of no-reflow/microvascular obstruction in the STEMI patient. Eur Heart J 38(47):3511–3513. https://doi.org/10.1093/eurheartj/ehx288
Broch K, Anstensrud AK, Woxholt S et al (2021) Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction. J Am Coll Cardiol 77(15):1845–1855. https://doi.org/10.1016/j.jacc.2021.02.049
Bulluck H, Carberry J, Carrick D et al (2022) A noncontrast CMR risk score for long-term risk stratification in reperfused ST-segment elevation myocardial infarction. JACC Cardiovasc Imaging 15(3):431–440. https://doi.org/10.1016/j.jcmg.2021.08.006
Tiller C, Reindl M, Holzknecht M et al (2022) Association of plasma interleukin-6 with infarct size, reperfusion injury, and adverse remodelling after ST-elevation myocardial infarction. Eur Heart J Acute Cardiovasc Care 11(2):113–123. https://doi.org/10.1093/ehjacc/zuab110
Li Z, Yin H, Wang D et al (2022) Prediction of microvascular obstruction by coronary artery angiography score after acute ST-segment elevation myocardial infarction: a single-center retrospective observational study. BMC Cardiovasc Disord 22(1):410. https://doi.org/10.1186/s12872-022-02836-x
Husser O, Monmeneu JV, Sanchis J et al (2013) Cardiovascular magnetic resonance-derived intramyocardial hemorrhage after STEMI: Influence on long-term prognosis, adverse left ventricular remodeling and relationship with microvascular obstruction. Int J Cardiol 167(5):2047–2054. https://doi.org/10.1016/j.ijcard.2012.05.055
Carrick D, Haig C, Ahmed N et al (2016) Temporal evolution of myocardial hemorrhage and edema in patients after acute ST-segment elevation myocardial infarction: pathophysiological insights and clinical implications. J Am Heart Assoc. https://doi.org/10.1161/JAHA.115.002834
Garg P, Broadbent DA, Swoboda PP et al (2017) Extra-cellular expansion in the normal, non-infarcted myocardium is associated with worsening of regional myocardial function after acute myocardial infarction. J Cardiovasc Magn Reson 19(1):73. https://doi.org/10.1186/s12968-017-0384-0
Homme RP, George AK, Singh M et al (2021) Mechanism of blood-heart-barrier leakage: implications for COVID-19 induced cardiovascular injury. Int J Mol Sci. https://doi.org/10.3390/ijms222413546
Li S, Chen J, Liu M et al (2021) Protective effect of HINT2 on mitochondrial function via repressing MCU complex activation attenuates cardiac microvascular ischemia-reperfusion injury. Basic Res Cardiol 116(1):65. https://doi.org/10.1007/s00395-021-00905-4
Tian F, Zhang Y (2021) Overexpression of SERCA2a alleviates cardiac microvascular ischemic injury by suppressing Mfn2-mediated ER/mitochondrial calcium tethering. Front Cell Dev Biol 9:636553. https://doi.org/10.3389/fcell.2021.636553
Fernandez-Jimenez R, Garcia-Prieto J, Sanchez-Gonzalez J et al (2015) Pathophysiology underlying the bimodal edema phenomenon after myocardial ischemia/reperfusion. J Am Coll Cardiol 66(7):816–828. https://doi.org/10.1016/j.jacc.2015.06.023
Kar S, Kavdia M (2011) Modeling of biopterin-dependent pathways of eNOS for nitric oxide and superoxide production. Free Radic Biol Med 51(7):1411–1427. https://doi.org/10.1016/j.freeradbiomed.2011.06.009
Jones SA, O’Donnell VB, Wood JD et al (1996) Expression of phagocyte NADPH oxidase components in human endothelial cells. Am J Physiol 271(4 Pt 2):H1626-1634. https://doi.org/10.1152/ajpheart.1996.271.4.H1626
Schroder K, Zhang M, Benkhoff S et al (2012) Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res 110(9):1217–1225. https://doi.org/10.1161/CIRCRESAHA.112.267054
Herring N, Tapoulal N, Kalla M et al (2019) Neuropeptide-Y causes coronary microvascular constriction and is associated with reduced ejection fraction following ST-elevation myocardial infarction. Eur Heart J 40(24):1920–1929. https://doi.org/10.1093/eurheartj/ehz115
Alex L, Frangogiannis NG (2019) Pericytes in the infarcted heart. Vasc Biol 1(1):H23–H31. https://doi.org/10.1530/VB-19-0007
Simonavicius N, Ashenden M, van Weverwijk A et al (2012) Pericytes promote selective vessel regression to regulate vascular patterning. Blood 120(7):1516–1527. https://doi.org/10.1182/blood-2011-01-332338
O’Farrell FM, Mastitskaya S, Hammond-Haley M et al (2017) Capillary pericytes mediate coronary no-reflow after myocardial ischaemia. Elife. https://doi.org/10.7554/eLife.29280
Shi Y, Hu G, Su J et al (2010) Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res 20(5):510–518. https://doi.org/10.1038/cr.2010.44
Stark K, Eckart A, Haidari S et al (2013) Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and “instruct” them with pattern-recognition and motility programs. Nat Immunol 14(1):41–51. https://doi.org/10.1038/ni.2477
Deckelbaum RA, Lobov IB, Cheung E et al (2020) The potassium channel Kcne3 is a VEGFA-inducible gene selectively expressed by vascular endothelial tip cells. Angiogenesis 23(2):179–192. https://doi.org/10.1007/s10456-019-09696-8
Bazzoni G, Dejana E (2004) Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84(3):869–901. https://doi.org/10.1152/physrev.00035.2003
Pohl U (2020) Connexins: key players in the control of vascular plasticity and function. Physiol Rev 100(2):525–572. https://doi.org/10.1152/physrev.00010.2019
Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7(1):41–53. https://doi.org/10.1038/nrn1824
Strauss RE, Gourdie RG (2020) Cx43 and the actin cytoskeleton: novel roles and implications for cell-cell junction-based barrier function regulation. Biomolecules. https://doi.org/10.3390/biom10121656
Yuan SY, Wu MH, Ustinova EE et al (2002) Myosin light chain phosphorylation in neutrophil-stimulated coronary microvascular leakage. Circ Res 90(11):1214–1221. https://doi.org/10.1161/01.res.0000020402.73609.f1
Shen Q, Rigor RR, Pivetti CD et al (2010) Myosin light chain kinase in microvascular endothelial barrier function. Cardiovasc Res 87(2):272–280. https://doi.org/10.1093/cvr/cvq144
Huang H, He J, Johnson D et al (2015) Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1alpha-VEGF pathway inhibition. Diabetes 64(1):200–212. https://doi.org/10.2337/db14-0016
Antonetti DA, Barber AJ, Hollinger LA et al (1999) Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 274(33):23463–23467. https://doi.org/10.1074/jbc.274.33.23463
Wang W, Lo ACY (2018) Diabetic retinopathy: pathophysiology and treatments. Int J Mol Sci. https://doi.org/10.3390/ijms19061816
Hilbert T, Klaschik S (2015) The angiopoietin/TIE receptor system: focusing its role for ischemia-reperfusion injury. Cytokine Growth Factor Rev 26(3):281–291. https://doi.org/10.1016/j.cytogfr.2014.10.013
Zhang Y, Kontos CD, Annex BH et al (2019) Angiopoietin-tie signaling pathway in endothelial cells: a computational model. iScience 20:497–511. https://doi.org/10.1016/j.isci.2019.10.006
Patel JV, Lim HS, Varughese GI et al (2008) Angiopoietin-2 levels as a biomarker of cardiovascular risk in patients with hypertension. Ann Med 40(3):215–222. https://doi.org/10.1080/07853890701779586
Rangasamy S, Srinivasan R, Maestas J et al (2011) A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy. Invest Ophthalmol Vis Sci 52(6):3784–3791. https://doi.org/10.1167/iovs.10-6386
Raza Z, Saleem U, Naureen Z (2020) Sphingosine 1-phosphate signaling in ischemia and reperfusion injury. Prostaglandins Other Lipid Mediat 149:106436. https://doi.org/10.1016/j.prostaglandins.2020.106436
Wilkerson BA (2014) The role of sphingosine-1-phosphate in endothelial barrier function. Biochim Biophys Acta 1841(10):1403–1412. https://doi.org/10.1016/j.bbalip.2014.06.012
Morel S, Christoffersen C, Axelsen LN et al (2016) Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43. Cardiovasc Res 109(3):385–396. https://doi.org/10.1093/cvr/cvw004
Alarcon-Martinez L, Villafranca-Baughman D, Quintero H et al (2020) Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature 585(7823):91–95. https://doi.org/10.1038/s41586-020-2589-x
Rodrigues SF, Granger DN (2010) Role of blood cells in ischaemia-reperfusion induced endothelial barrier failure. Cardiovasc Res 87(2):291–299. https://doi.org/10.1093/cvr/cvq090
Dorge H, Neumann T, Behrends M et al (2000) Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation. Am J Physiol Heart Circ Physiol 279(6):H2587-2592. https://doi.org/10.1152/ajpheart.2000.279.6.H2587
Giordano G, Napolitano M, Cellurale M et al (2022) Circulating endothelial cell levels correlate with treatment outcomes of splanchnic vein thrombosis in patients with chronic myeloproliferative neoplasms. J Pers Med. https://doi.org/10.3390/jpm12030364
Damani S, Bacconi A, Libiger O et al (2012) Characterization of circulating endothelial cells in acute myocardial infarction. Sci Transl Med 4(126):126ea133. https://doi.org/10.1126/scitranslmed.3003451
Chen CW, Wang LL, Zaman S et al (2018) Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction. Cardiovasc Res 114(7):1029–1040. https://doi.org/10.1093/cvr/cvy067
Ridger VC, Boulanger CM, Angelillo-Scherrer A et al (2017) Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology. Thromb Haemost 117(7):1296–1316. https://doi.org/10.1160/TH16-12-0943
Zhang J, Zhu Y, Wu Y et al (2020) Synergistic effects of EMPs and PMPs on pulmonary vascular leakage and lung injury after ischemia/reperfusion. Cell Commun Signal 18(1):184. https://doi.org/10.1186/s12964-020-00672-0
Li F, Liu D, Liu M et al (2022) Tregs biomimetic nanoparticle to reprogram inflammatory and redox microenvironment in infarct tissue to treat myocardial ischemia reperfusion injury in mice. J Nanobiotechnology 20(1):251. https://doi.org/10.1186/s12951-022-01445-2
Kloner RA, Giacomelli F, Alker KJ et al (1991) Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion. Circulation 84(4):1758–1772. https://doi.org/10.1161/01.cir.84.4.1758
Ge L, Zhou X, Ji WJ et al (2015) Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. Am J Physiol Heart Circ Physiol 308(5):H500-509. https://doi.org/10.1152/ajpheart.00381.2014
Coenen DM, Mastenbroek TG, Cosemans J (2017) Platelet interaction with activated endothelium: mechanistic insights from microfluidics. Blood 130(26):2819–2828. https://doi.org/10.1182/blood-2017-04-780825
Schanze N, Bode C, Duerschmied D (2019) Platelet contributions to myocardial ischemia/reperfusion injury. Front Immunol 10:1260. https://doi.org/10.3389/fimmu.2019.01260
Konijnenberg LSF, Damman P, Duncker DJ et al (2020) Pathophysiology and diagnosis of coronary microvascular dysfunction in ST-elevation myocardial infarction. Cardiovasc Res 116(4):787–805. https://doi.org/10.1093/cvr/cvz301
Rasola A, Bernardi P (2011) Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium 50(3):222–233. https://doi.org/10.1016/j.ceca.2011.04.007
Orrenius S, Gogvadze V, Zhivotovsky B (2015) Calcium and mitochondria in the regulation of cell death. Biochem Biophys Res Commun 460(1):72–81. https://doi.org/10.1016/j.bbrc.2015.01.137
Li C, Ma Q, Toan S et al (2020) SERCA overexpression reduces reperfusion-mediated cardiac microvascular damage through inhibition of the calcium/MCU/mPTP/necroptosis signaling pathways. Redox Biol 36:101659. https://doi.org/10.1016/j.redox.2020.101659
Alevriadou BR, Patel A, Noble M et al (2021) Molecular nature and physiological role of the mitochondrial calcium uniporter channel. Am J Physiol Cell Physiol 320(4):C465–C482. https://doi.org/10.1152/ajpcell.00502.2020
Tanwar J, Singh JB, Motiani RK (2021) Molecular machinery regulating mitochondrial calcium levels: the nuts and bolts of mitochondrial calcium dynamics. Mitochondrion 57:9–22. https://doi.org/10.1016/j.mito.2020.12.001
Raffaello A, De Stefani D, Sabbadin D et al (2013) The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 32(17):2362–2376. https://doi.org/10.1038/emboj.2013.157
Wu L, Tan JL, Chen ZY et al (2019) Cardioprotection of post-ischemic moderate ROS against ischemia/reperfusion via STAT3-induced the inhibition of MCU opening. Basic Res Cardiol 114(5):39. https://doi.org/10.1007/s00395-019-0747-9
Gambardella J, Trimarco B, Iaccarino G et al (2018) New insights in cardiac calcium handling and excitation-contraction coupling. Adv Exp Med Biol 1067:373–385. https://doi.org/10.1007/5584_2017_106
Gwathmey JK, Yerevanian AI, Hajjar RJ (2011) Cardiac gene therapy with SERCA2a: from bench to bedside. J Mol Cell Cardiol 50(5):803–812. https://doi.org/10.1016/j.yjmcc.2010.11.011
Periasamy M, Kalyanasundaram A (2007) SERCA pump isoforms: their role in calcium transport and disease. Muscle Nerve 35(4):430–442. https://doi.org/10.1002/mus.20745
Chen L, Sun Q, Zhou D et al (2017) HINT2 triggers mitochondrial Ca(2+) influx by regulating the mitochondrial Ca(2+) uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer. Cancer Lett 411:106–116. https://doi.org/10.1016/j.canlet.2017.09.020
Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081–1086. https://doi.org/10.1126/science.1209038
Nie X, Tang W, Zhang Z et al (2020) Procyanidin B2 mitigates endothelial endoplasmic reticulum stress through a PPARdelta-Dependent mechanism. Redox Biol 37:101728. https://doi.org/10.1016/j.redox.2020.101728
Battson ML, Lee DM, Gentile CL (2017) Endoplasmic reticulum stress and the development of endothelial dysfunction. Am J Physiol Heart Circ Physiol 312(3):H355–H367. https://doi.org/10.1152/ajpheart.00437.2016
Cao SS, Kaufman RJ (2014) Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal 21(3):396–413. https://doi.org/10.1089/ars.2014.5851
Rizzuto R, De Stefani D, Raffaello A et al (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13(9):566–578. https://doi.org/10.1038/nrm3412
Rainbolt TK, Saunders JM, Wiseman RL (2014) Stress-responsive regulation of mitochondria through the ER unfolded protein response. Trends Endocrinol Metab 25(10):528–537. https://doi.org/10.1016/j.tem.2014.06.007
He X, Bi XY, Lu XZ et al (2015) Reduction of mitochondria-endoplasmic reticulum interactions by acetylcholine protects human umbilical vein endothelial cells from hypoxia/reoxygenation injury. Arterioscler Thromb Vasc Biol 35(7):1623–1634. https://doi.org/10.1161/ATVBAHA.115.305469
Kirkman DL, Robinson AT, Rossman MJ et al (2021) Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases. Am J Physiol Heart Circ Physiol 320(5):H2080–H2100. https://doi.org/10.1152/ajpheart.00917.2020
Daiber A, Andreadou I, Oelze M et al (2021) Discovery of new therapeutic redox targets for cardioprotection against ischemia/reperfusion injury and heart failure. Free Radic Biol Med 163:325–343. https://doi.org/10.1016/j.freeradbiomed.2020.12.026
Jiang X, Wu D, Jiang Z et al (2021) Protective effect of nicorandil on cardiac microvascular injury: role of mitochondrial integrity. Oxid Med Cell Longev 2021:4665632. https://doi.org/10.1155/2021/4665632
Maier-Begandt D, Comstra HS, Molina SA et al (2021) A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFalpha-induced increases in endothelial permeability. Sci Signal. https://doi.org/10.1126/scisignal.aba2940
Zhou H, Hu S, Jin Q et al (2017) Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening. J Am Heart Assoc. https://doi.org/10.1161/JAHA.116.005328
Kalia R, Wang RY, Yusuf A et al (2018) Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature 558(7710):401–405. https://doi.org/10.1038/s41586-018-0211-2
Kraus F, Roy K, Pucadyil TJ et al (2021) Function and regulation of the divisome for mitochondrial fission. Nature 590(7844):57–66. https://doi.org/10.1038/s41586-021-03214-x
Yu Y, Peng XD, Qian XJ et al (2021) Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis. Signal Transduct Target Ther 6(1):401. https://doi.org/10.1038/s41392-021-00790-2
Chen Y, Li S, Zhang Y et al (2021) The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p/Mfn1 axis-mediated mitochondrial dynamics. Redox Biol 41:101910. https://doi.org/10.1016/j.redox.2021.101910
Depoix CL, Colson A, Hubinont C et al (2020) Impaired vascular endothelial growth factor expression and secretion during in vitro differentiation of human primary term cytotrophoblasts. Angiogenesis 23(2):221–230. https://doi.org/10.1007/s10456-019-09702-z
Damico R, Zulueta JJ, Hassoun PM (2012) Pulmonary endothelial cell NOX. Am J Respir Cell Mol Biol 47(2):129–139. https://doi.org/10.1165/rcmb.2010-0331RT
Heusch G, Boengler K, Schulz R (2010) Inhibition of mitochondrial permeability transition pore opening: the Holy Grail of cardioprotection. Basic Res Cardiol 105(2):151–154. https://doi.org/10.1007/s00395-009-0080-9
Zhou H, Shi C, Hu S et al (2018) BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis 21(3):599–615. https://doi.org/10.1007/s10456-018-9611-z
Zhou H, Wang J, Zhu P et al (2018) Ripk3 regulates cardiac microvascular reperfusion injury: The role of IP3R-dependent calcium overload, XO-mediated oxidative stress and F-action/filopodia-based cellular migration. Cell Signal 45:12–22. https://doi.org/10.1016/j.cellsig.2018.01.020
Zhou H, Wang J, Zhu P et al (2018) NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2alpha. Basic Res Cardiol 113(4):23. https://doi.org/10.1007/s00395-018-0682-1
Kwong JQ, Davis J, Baines CP et al (2014) Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21(8):1209–1217. https://doi.org/10.1038/cdd.2014.36
Zhu H, Toan S, Mui D et al (2021) Mitochondrial quality surveillance as a therapeutic target in myocardial infarction. Acta Physiol (Oxf) 231(3):e13590. https://doi.org/10.1111/apha.13590
Zhou H, Ren J, Toan S et al (2021) Role of mitochondrial quality surveillance in myocardial infarction: From bench to bedside. Ageing Res Rev 66:101250. https://doi.org/10.1016/j.arr.2020.101250
Song Y, Xing H, He Y et al (2021) Inhibition of mitochondrial reactive oxygen species improves coronary endothelial function after cardioplegic hypoxia/reoxygenation. J Thorac Cardiovasc Surg. https://doi.org/10.1016/j.jtcvs.2021.06.029
Chen Y, Liu C, Zhou P et al (2021) Coronary Endothelium No-Reflow Injury Is Associated with ROS-Modified Mitochondrial Fission through the JNK-Drp1 Signaling Pathway. Oxid Med Cell Longev 2021:6699516. https://doi.org/10.1155/2021/6699516
Ribeiro LF, Catarino T, Carvalho M et al (2021) Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation. Sci Signal. https://doi.org/10.1126/scisignal.abb1953
Skyschally A, Amanakis G, Neuhauser M et al (2017) Impact of electrical defibrillation on infarct size and no-reflow in pigs subjected to myocardial ischemia-reperfusion without and with ischemic conditioning. Am J Physiol Heart Circ Physiol 313(5):H871–H878. https://doi.org/10.1152/ajpheart.00293.2017
Chang X, Li Y, Cai C et al (2022) Mitochondrial quality control mechanisms as molecular targets in diabetic heart. Metabolism 137:155313. https://doi.org/10.1016/j.metabol.2022.155313
Jin H, Zhu Y, Li Y et al (2019) BDNF-mediated mitophagy alleviates high-glucose-induced brain microvascular endothelial cell injury. Apoptosis 24(5–6):511–528. https://doi.org/10.1007/s10495-019-01535-x
Zheng J, Lu C (2020) Oxidized LDL Causes Endothelial Apoptosis by Inhibiting Mitochondrial Fusion and Mitochondria Autophagy. Front Cell Dev Biol 8:600950. https://doi.org/10.3389/fcell.2020.600950
Sun L, Hao Y, An R et al (2014) Overexpression of Rcan1–1L inhibits hypoxia-induced cell apoptosis through induction of mitophagy. Mol Cells 37(11):785–794. https://doi.org/10.14348/molcells.2014.0103
Zhou H, Zhang Y, Hu S et al (2017) Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis. J Pineal Res. https://doi.org/10.1111/jpi.12413
Bravo-San Pedro JM, Kroemer G, Galluzzi L (2017) Autophagy and mitophagy in cardiovascular disease. Circ Res 120(11):1812–1824. https://doi.org/10.1161/CIRCRESAHA.117.311082
Battistutta R, Lolli G (2011) Structural and functional determinants of protein kinase CK2alpha: facts and open questions. Mol Cell Biochem 356(1–2):67–73. https://doi.org/10.1007/s11010-011-0939-6
Chen G, Han Z, Feng D et al (2014) A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell 54(3):362–377. https://doi.org/10.1016/j.molcel.2014.02.034
Zhou H, Zhu P, Wang J et al (2018) Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2alpha-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell Death Differ 25(6):1080–1093. https://doi.org/10.1038/s41418-018-0086-7
Gao XM, Su Y, Moore S et al (2019) Relaxin mitigates microvascular damage and inflammation following cardiac ischemia-reperfusion. Basic Res Cardiol 114(4):30. https://doi.org/10.1007/s00395-019-0739-9
Gao XM, Wang BH, Woodcock E et al (2000) Expression of active alpha(1B)-adrenergic receptors in the heart does not alleviate ischemic reperfusion injury. J Mol Cell Cardiol 32(9):1679–1686. https://doi.org/10.1006/jmcc.2000.1201
Gao XM, Liu Y, White D et al (2011) Deletion of macrophage migration inhibitory factor protects the heart from severe ischemia-reperfusion injury: a predominant role of anti-inflammation. J Mol Cell Cardiol 50(6):991–999. https://doi.org/10.1016/j.yjmcc.2010.12.022
Gao XM, Moore XL, Liu Y et al (2016) Splenic release of platelets contributes to increased circulating platelet size and inflammation after myocardial infarction. Clin Sci (Lond) 130(13):1089–1104. https://doi.org/10.1042/CS20160234
McLaughlin MG, Stone GW, Aymong E et al (2004) Prognostic utility of comparative methods for assessment of ST-segment resolution after primary angioplasty for acute myocardial infarction: the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. J Am Coll Cardiol 44(6):1215–1223. https://doi.org/10.1016/j.jacc.2004.06.053
Karamasis GV, Russhard P, Al Janabi F et al (2018) Peri-procedural ST segment resolution during Primary Percutaneous Coronary Intervention (PPCI) for acute myocardial infarction: predictors and clinical consequences. J Electrocardiol 51(2):224–229. https://doi.org/10.1016/j.jelectrocard.2017.09.011
Bethke A, Halvorsen S, Bohmer E et al (2015) Myocardial perfusion grade predicts final infarct size and left ventricular function in patients with ST-elevation myocardial infarction treated with a pharmaco-invasive strategy (thrombolysis and early angioplasty). EuroIntervention 11(5):518–524. https://doi.org/10.4244/EIJY15M04_02
Roubille F, Mewton N, Elbaz M et al (2014) No post-conditioning in the human heart with thrombolysis in myocardial infarction flow 2–3 on admission. Eur Heart J 35(25):1675–1682. https://doi.org/10.1093/eurheartj/ehu054
Moroni F, Azzalini L, Caixeta A et al (2022) TIMI flow and myocardial blushing after rescue PCI and cardiac magnetic resonance: results from the Myocardial Salvage After Rescue Angioplasty: Evaluation by Magnetic Resonance (SAVE-ME) study. Int J Cardiol. https://doi.org/10.1016/j.ijcard.2022.08.014
Ellis SG, Topol EJ, Gallison L et al (1988) Predictors of success for coronary angioplasty performed for acute myocardial infarction. J Am Coll Cardiol 12(6):1407–1415. https://doi.org/10.1016/s0735-1097(88)80003-2
Ge H, Ding S, An D et al (2016) Frame counting improves the assessment of post-reperfusion microvascular patency by TIMI myocardial perfusion grade: evidence from cardiac magnetic resonance imaging. Int J Cardiol 203:360–366. https://doi.org/10.1016/j.ijcard.2015.10.194
Bailleul C, Aissaoui N, Cayla G et al (2018) Prognostic impact of prepercutaneous coronary intervention TIMI flow in patients with ST-segment and non-ST-segment elevation myocardial infarction: Results from the FAST-MI 2010 registry. Arch Cardiovasc Dis 111(2):101–108. https://doi.org/10.1016/j.acvd.2017.04.004
Joost A, Stiermaier T, Eitel C et al (2016) Impact of initial culprit vessel flow on infarct size, microvascular obstruction, and myocardial salvage in acute reperfused ST-elevation myocardial infarction. Am J Cardiol 118(9):1316–1322. https://doi.org/10.1016/j.amjcard.2016.07.056
Gibson CM, Cannon CP, Daley WL et al (1996) TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 93(5):879–888. https://doi.org/10.1161/01.cir.93.5.879
Jiang L, Yao H, Liang ZG (2017) Postoperative assessment of myocardial function and microcirculation in patients with acute coronary syndrome by myocardial contrast echocardiography. Med Sci Monit 23:2324–2332. https://doi.org/10.12659/msm.901233
Verkaik M, van Poelgeest EM, Kwekkeboom RFJ et al (2018) Myocardial contrast echocardiography in mice: technical and physiological aspects. Am J Physiol Heart Circ Physiol 314(3):H381–H391. https://doi.org/10.1152/ajpheart.00242.2017
Aggarwal S, Xie F, High R et al (2018) Prevalence and predictive value of microvascular flow abnormalities after successful contemporary percutaneous coronary intervention in acute ST-segment elevation myocardial infarction. J Am Soc Echocardiogr 31(6):674–682. https://doi.org/10.1016/j.echo.2018.01.009
Greaves K, Dixon SR, Fejka M et al (2003) Myocardial contrast echocardiography is superior to other known modalities for assessing myocardial reperfusion after acute myocardial infarction. Heart 89(2):139–144. https://doi.org/10.1136/heart.89.2.139
Reinstadler SJ, Thiele H, Eitel I (2015) Risk stratification by cardiac magnetic resonance imaging after ST-elevation myocardial infarction. Curr Opin Cardiol 30(6):681–689. https://doi.org/10.1097/HCO.0000000000000227
Stiermaier T, Jobs A, de Waha S et al (2017) Optimized prognosis assessment in ST-segment-elevation myocardial infarction using a cardiac magnetic resonance imaging risk score. Circ Cardiovasc Imaging. https://doi.org/10.1161/CIRCIMAGING.117.006774
Eitel I, de Waha S, Wohrle J et al (2014) Comprehensive prognosis assessment by CMR imaging after ST-segment elevation myocardial infarction. J Am Coll Cardiol 64(12):1217–1226. https://doi.org/10.1016/j.jacc.2014.06.1194
Zhou D, Xu J, Zhao S et al (2020) CMR publications from China of the last more than 30 years. Int J Cardiovasc Imaging 36(9):1737–1747. https://doi.org/10.1007/s10554-020-01873-x
Perazzolo Marra M, Lima JA, Iliceto S (2011) MRI in acute myocardial infarction. Eur Heart J 32(3):284–293. https://doi.org/10.1093/eurheartj/ehq409
Cerqueira MD, Weissman NJ, Dilsizian V et al (2002) Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 105(4):539–542. https://doi.org/10.1161/hc0402.102975
Higgins CB, Herfkens R, Lipton MJ et al (1983) Nuclear magnetic resonance imaging of acute myocardial infarction in dogs: alterations in magnetic relaxation times. Am J Cardiol 52(1):184–188. https://doi.org/10.1016/0002-9149(83)90093-0
Aletras AH, Tilak GS, Natanzon A et al (2006) Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation 113(15):1865–1870. https://doi.org/10.1161/CIRCULATIONAHA.105.576025
Simonetti OP, Finn JP, White RD et al (1996) “Black blood” T2-weighted inversion-recovery MR imaging of the heart. Radiology 199(1):49–57. https://doi.org/10.1148/radiology.199.1.8633172
Friedrich MG, Abdel-Aty H, Taylor A et al (2008) The salvaged area at risk in reperfused acute myocardial infarction as visualized by cardiovascular magnetic resonance. J Am Coll Cardiol 51(16):1581–1587. https://doi.org/10.1016/j.jacc.2008.01.019
Reinstadler SJ, Stiermaier T, Fuernau G et al (2016) The challenges and impact of microvascular injury in ST-elevation myocardial infarction. Expert Rev Cardiovasc Ther 14(4):431–443. https://doi.org/10.1586/14779072.2016.1135055
Shin JM, Choi EY, Park CH et al (2020) Quantitative T1 mapping for detecting microvascular obstruction in reperfused acute myocardial infarction: comparison with late gadolinium enhancement imaging. Korean J Radiol 21(8):978–986. https://doi.org/10.3348/kjr.2019.0736
Simonetti OP, Kim RJ, Fieno DS et al (2001) An improved MR imaging technique for the visualization of myocardial infarction. Radiology 218(1):215–223. https://doi.org/10.1148/radiology.218.1.r01ja50215
Dastidar AG, Harries I, Pontecorboli G et al (2019) Native T1 mapping to detect extent of acute and chronic myocardial infarction: comparison with late gadolinium enhancement technique. Int J Cardiovasc Imaging 35(3):517–527. https://doi.org/10.1007/s10554-018-1467-1
Judd RM, Lugo-Olivieri CH, Arai M et al (1995) Physiological basis of myocardial contrast enhancement in fast magnetic resonance images of 2-day-old reperfused canine infarcts. Circulation 92(7):1902–1910. https://doi.org/10.1161/01.cir.92.7.1902
Ibrahim T, Nekolla SG, Hornke M et al (2005) Quantitative measurement of infarct size by contrast-enhanced magnetic resonance imaging early after acute myocardial infarction: comparison with single-photon emission tomography using Tc99m-sestamibi. J Am Coll Cardiol 45(4):544–552. https://doi.org/10.1016/j.jacc.2004.10.058
Kirschner R, Varga-Szemes A, Brott BC et al (2011) Quantification of myocardial viability distribution with Gd(DTPA) bolus-enhanced, signal intensity-based percent infarct mapping. Magn Reson Imaging 29(5):650–658. https://doi.org/10.1016/j.mri.2011.02.010
McAlindon E, Pufulete M, Lawton C et al (2015) Quantification of infarct size and myocardium at risk: evaluation of different techniques and its implications. Eur Heart J Cardiovasc Imaging 16(7):738–746. https://doi.org/10.1093/ehjci/jev001
Stone GW, Selker HP, Thiele H et al (2016) Relationship between infarct size and outcomes following primary PCI: patient-level analysis from 10 randomized trials. J Am Coll Cardiol 67(14):1674–1683. https://doi.org/10.1016/j.jacc.2016.01.069
Wu KC, Kim RJ, Bluemke DA et al (1998) Quantification and time course of microvascular obstruction by contrast-enhanced echocardiography and magnetic resonance imaging following acute myocardial infarction and reperfusion. J Am Coll Cardiol 32(6):1756–1764. https://doi.org/10.1016/s0735-1097(98)00429-x
Bulluck H, Dharmakumar R, Arai AE et al (2018) Cardiovascular magnetic resonance in acute ST-segment-elevation myocardial infarction: recent advances, controversies, and future directions. Circulation 137(18):1949–1964. https://doi.org/10.1161/CIRCULATIONAHA.117.030693
Lima JA, Judd RM, Bazille A et al (1995) Regional heterogeneity of human myocardial infarcts demonstrated by contrast-enhanced MRI. Potential mechanisms. Circulation 92(5):1117–1125. https://doi.org/10.1161/01.cir.92.5.1117
Hombach V, Grebe O, Merkle N et al (2005) Sequelae of acute myocardial infarction regarding cardiac structure and function and their prognostic significance as assessed by magnetic resonance imaging. Eur Heart J 26(6):549–557. https://doi.org/10.1093/eurheartj/ehi147
Garcia-Dorado D, Oliveras J, Gili J et al (1993) Analysis of myocardial oedema by magnetic resonance imaging early after coronary artery occlusion with or without reperfusion. Cardiovasc Res 27(8):1462–1469. https://doi.org/10.1093/cvr/27.8.1462
Boxt LM, Hsu D, Katz J et al (1993) Estimation of myocardial water content using transverse relaxation time from dual spin-echo magnetic resonance imaging. Magn Reson Imaging 11(3):375–383. https://doi.org/10.1016/0730-725x(93)90070-t
Robbers LF, Eerenberg ES, Teunissen PF et al (2013) Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial infarction represent microvascular destruction and haemorrhage. Eur Heart J 34(30):2346–2353. https://doi.org/10.1093/eurheartj/eht100
O’Regan DP, Ahmed R, Karunanithy N et al (2009) Reperfusion hemorrhage following acute myocardial infarction: assessment with T2* mapping and effect on measuring the area at risk. Radiology 250(3):916–922. https://doi.org/10.1148/radiol.2503081154
Walsh SR, Tang TY, Kullar P et al (2008) Ischaemic preconditioning during cardiac surgery: systematic review and meta-analysis of perioperative outcomes in randomised clinical trials. Eur J Cardiothorac Surg 34(5):985–994. https://doi.org/10.1016/j.ejcts.2008.07.062
Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116(4):674–699. https://doi.org/10.1161/CIRCRESAHA.116.305348
Liu J, Gu Y, Guo M et al (2021) Neuroprotective effects and mechanisms of ischemic/hypoxic preconditioning on neurological diseases. CNS Neurosci Ther 27(8):869–882. https://doi.org/10.1111/cns.13642
Wever KE, Menting TP, Rovers M et al (2012) Ischemic preconditioning in the animal kidney, a systematic review and meta-analysis. PLoS ONE 7(2):e32296. https://doi.org/10.1371/journal.pone.0032296
Lee JH, You HJ, Lee TY et al (2022) Current status of experimental animal skin flap models: ischemic preconditioning and molecular factors. Int J Mol Sci. https://doi.org/10.3390/ijms23095234
Ruze A, Chen BD, Liu F et al (2019) Macrophage migration inhibitory factor plays an essential role in ischemic preconditioning-mediated cardioprotection. Clin Sci (Lond) 133(5):665–680. https://doi.org/10.1042/CS20181013
Cutrn JC, Perrelli MG, Cavalieri B et al (2002) Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning. Free Radic Biol Med 33(9):1200–1208. https://doi.org/10.1016/s0891-5849(02)01017-1
Lin WY, Chang YC, Ho CJ et al (2013) Ischemic preconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatal brain. Stroke 44(1):162–169. https://doi.org/10.1161/STROKEAHA.112.677617
Zhao ZQ, Corvera JS, Halkos ME et al (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285(2):H579-588. https://doi.org/10.1152/ajpheart.01064.2002
You J, Feng L, Xin M et al (2018) Cerebral ischemic postconditioning plays a neuroprotective role through regulation of central and peripheral glutamate. Biomed Res Int 2018:6316059. https://doi.org/10.1155/2018/6316059
Guo L, Xu JM, Mo XY (2015) Ischemic postconditioning regulates cardiomyocyte autophagic activity following ischemia/reperfusion injury. Mol Med Rep 12(1):1169–1176. https://doi.org/10.3892/mmr.2015.3533
Dong M, Mu N, Guo F et al (2014) The beneficial effects of postconditioning on no-reflow phenomenon after percutaneous coronary intervention in patients with ST-elevation acute myocardial infarction. J Thromb Thrombolysis 38(2):208–214. https://doi.org/10.1007/s11239-013-1010-0
Li CY, Ma W, Liu KP et al (2021) Advances in intervention methods and brain protection mechanisms of in situ and remote ischemic postconditioning. Metab Brain Dis 36(1):53–65. https://doi.org/10.1007/s11011-020-00562-x
Liu C, Yang J, Zhang C et al (2020) Remote ischemic conditioning reduced cerebral ischemic injury by modulating inflammatory responses and ERK activity in type 2 diabetic mice. Neurochem Int 135:104690. https://doi.org/10.1016/j.neuint.2020.104690
Zhou CC, Yao WT, Ge YZ et al (2017) Remote ischemic conditioning for the prevention of contrast-induced acute kidney injury in patients undergoing intravascular contrast administration: a meta-analysis and trial sequential analysis of 16 randomized controlled trials. Oncotarget 8(45):79323–79336. https://doi.org/10.18632/oncotarget.18106
Min F, Jia XJ, Gao Q et al (2020) Remote ischemic post-conditioning protects against myocardial ischemia/reperfusion injury by inhibiting the Rho-kinase signaling pathway. Exp Ther Med 19(1):99–106. https://doi.org/10.3892/etm.2019.8176
Sluijter JPG, Davidson SM, Boulanger CM et al (2018) Extracellular vesicles in diagnostics and therapy of the ischaemic heart: position paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 114(1):19–34. https://doi.org/10.1093/cvr/cvx211
Loyer X, Vion AC, Tedgui A et al (2014) Microvesicles as cell-cell messengers in cardiovascular diseases. Circ Res 114(2):345–353. https://doi.org/10.1161/CIRCRESAHA.113.300858
Boulanger CM, Scoazec A, Ebrahimian T et al (2001) Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 104(22):2649–2652. https://doi.org/10.1161/hc4701.100516
Porto I, Biasucci LM, De Maria GL et al (2012) Intracoronary microparticles and microvascular obstruction in patients with ST elevation myocardial infarction undergoing primary percutaneous intervention. Eur Heart J 33(23):2928–2938. https://doi.org/10.1093/eurheartj/ehs065
Baranyai T, Giricz Z, Varga ZV et al (2017) In vivo MRI and ex vivo histological assessment of the cardioprotection induced by ischemic preconditioning, postconditioning and remote conditioning in a closed-chest porcine model of reperfused acute myocardial infarction: importance of microvasculature. J Transl Med 15(1):67. https://doi.org/10.1186/s12967-017-1166-z
White SK, Frohlich GM, Sado DM et al (2015) Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 8(1 Pt B):178–188. https://doi.org/10.1016/j.jcin.2014.05.015
Eitel I, Stiermaier T, Rommel KP et al (2015) Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial. Eur Heart J 36(44):3049–3057. https://doi.org/10.1093/eurheartj/ehv463
Goerg J, Sommerfeld M, Greiner B et al (2021) Low-Dose empagliflozin improves systolic heart function after myocardial infarction in rats: regulation of MMP9, NHE1, and SERCA2a. Int J Mol Sci. https://doi.org/10.3390/ijms22115437
Wright EM, Loo DD, Hirayama BA (2011) Biology of human sodium glucose transporters. Physiol Rev 91(2):733–794. https://doi.org/10.1152/physrev.00055.2009
Sinha B, Ghosal S (2019) Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduce hospitalization for heart failure only and have no effect on atherosclerotic cardiovascular events: a meta-analysis. Diabetes Ther 10(3):891–899. https://doi.org/10.1007/s13300-019-0597-3
Mahaffey KW, Neal B, Perkovic V et al (2018) Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 137(4):323–334. https://doi.org/10.1161/CIRCULATIONAHA.117.032038
Wiviott SD, Raz I, Bonaca MP et al (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380(4):347–357. https://doi.org/10.1056/NEJMoa1812389
Norhammar A, Bodegard J, Nystrom T et al (2019) Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE-TIMI 58 trial: a nationwide observational study. Diabetes Obes Metab 21(5):1136–1145. https://doi.org/10.1111/dom.13627
Fathi A, Vickneson K, Singh JS (2021) SGLT2-inhibitors; more than just glycosuria and diuresis. Heart Fail Rev 26(3):623–642. https://doi.org/10.1007/s10741-020-10038-w
Ceriello A, Ofstad AP, Zwiener I et al (2020) Empagliflozin reduced long-term HbA1c variability and cardiovascular death: insights from the EMPA-REG OUTCOME trial. Cardiovasc Diabetol 19(1):176. https://doi.org/10.1186/s12933-020-01147-9
Park SH, Belcastro E, Hasan H et al (2021) Angiotensin II-induced upregulation of SGLT1 and 2 contributes to human microparticle-stimulated endothelial senescence and dysfunction: protective effect of gliflozins. Cardiovasc Diabetol 20(1):65. https://doi.org/10.1186/s12933-021-01252-3
Ma L, Zou R, Shi W et al (2022) SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways. Theranostics 12(11):5034–5050. https://doi.org/10.7150/thno.75121
Tian J, Zhang M, Suo M et al (2021) Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKalpha/TGF-beta/Smad signalling in type 2 diabetic rats. J Cell Mol Med 25(16):7642–7659. https://doi.org/10.1111/jcmm.16601
Kolijn D, Pabel S, Tian Y et al (2021) Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Galpha oxidation. Cardiovasc Res 117(2):495–507. https://doi.org/10.1093/cvr/cvaa123
Aragon-Herrera A, Feijoo-Bandin S, Anido-Varela L et al (2022) Relaxin-2 as a potential biomarker in cardiovascular diseases. J Pers Med. https://doi.org/10.3390/jpm12071021
Du XJ, Bathgate RA, Samuel CS et al (2010) Cardiovascular effects of relaxin: from basic science to clinical therapy. Nat Rev Cardiol 7(1):48–58. https://doi.org/10.1038/nrcardio.2009.198
Samuel CS, Du XJ, Bathgate RA et al (2006) “Relaxin” the stiffened heart and arteries: the therapeutic potential for relaxin in the treatment of cardiovascular disease. Pharmacol Ther 112(2):529–552. https://doi.org/10.1016/j.pharmthera.2005.05.012
Bathgate RA, Halls ML, van der Westhuizen ET et al (2013) Relaxin family peptides and their receptors. Physiol Rev 93(1):405–480. https://doi.org/10.1152/physrev.00001.2012
Hsu SY, Nakabayashi K, Nishi S et al (2002) Activation of orphan receptors by the hormone relaxin. Science 295(5555):671–674. https://doi.org/10.1126/science.1065654
Martin B, Romero G, Salama G (2019) Cardioprotective actions of relaxin. Mol Cell Endocrinol 487:45–53. https://doi.org/10.1016/j.mce.2018.12.016
Pini A, Boccalini G, Baccari MC et al (2016) Protection from cigarette smoke-induced vascular injury by recombinant human relaxin-2 (serelaxin). J Cell Mol Med 20(5):891–902. https://doi.org/10.1111/jcmm.12802
Gao S, Li L, Li L et al (2019) Effects of the combination of tanshinone IIA and puerarin on cardiac function and inflammatory response in myocardial ischemia mice. J Mol Cell Cardiol 137:59–70. https://doi.org/10.1016/j.yjmcc.2019.09.012
Uto T, Tung NH, Ohta T et al (2018) Antiproliferative activity and apoptosis induction by trijuganone C isolated from the root of Salvia miltiorrhiza Bunge (Danshen). Phytother Res 32(4):657–666. https://doi.org/10.1002/ptr.6013
Zhou R, He LF, Li YJ et al (2012) Cardioprotective effect of water and ethanol extract of Salvia miltiorrhiza in an experimental model of myocardial infarction. J Ethnopharmacol 139(2):440–446. https://doi.org/10.1016/j.jep.2011.11.030
Irmak F, Kurt Yazar S, Sirvan SS et al (2018) Beneficial effects of Salvia miltiorrhiza in the healing of burn wounds: an experimental study in rats. J Plast Surg Hand Surg 52(4):229–233. https://doi.org/10.1080/2000656X.2018.1461631
Fei YX, Wang SQ, Yang LJ et al (2017) Salvia miltiorrhiza Bunge (Danshen) extract attenuates permanent cerebral ischemia through inhibiting platelet activation in rats. J Ethnopharmacol 207:57–66. https://doi.org/10.1016/j.jep.2017.06.023
Guo R, Li L, Su J et al (2020) Pharmacological activity and mechanism of tanshinone IIA in related diseases. Drug Des Devel Ther 14:4735–4748. https://doi.org/10.2147/DDDT.S266911
Hung YC, Pan TL, Hu WL (2016) Roles of reactive oxygen species in anticancer therapy with Salvia miltiorrhiza bunge. Oxid Med Cell Longev 2016:5293284. https://doi.org/10.1155/2016/5293284
Chen L, Guo QH, Chang Y et al (2017) Tanshinone IIA ameliorated endothelial dysfunction in rats with chronic intermittent hypoxia. Cardiovasc Pathol 31:47–53. https://doi.org/10.1016/j.carpath.2017.06.008
Mo J, Yang R, Li F et al (2018) Scutellarin protects against vascular endothelial dysfunction and prevents atherosclerosis via antioxidation. Phytomedicine 42:66–74. https://doi.org/10.1016/j.phymed.2018.03.021
Xi J, Rong Y, Zhao Z et al (2021) Scutellarin ameliorates high glucose-induced vascular endothelial cells injury by activating PINK1/Parkin-mediated mitophagy. J Ethnopharmacol 271:113855. https://doi.org/10.1016/j.jep.2021.113855
Mondal NK, Behera J, Kelly KE et al (2019) Tetrahydrocurcumin epigenetically mitigates mitochondrial dysfunction in brain vasculature during ischemic stroke. Neurochem Int 122:120–138. https://doi.org/10.1016/j.neuint.2018.11.015
Vacek JC, Behera J, George AK et al (2018) Tetrahydrocurcumin ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells. J Cell Physiol 233(4):3080–3092. https://doi.org/10.1002/jcp.26145
Duan H, Zhang Q, Liu J et al (2021) Suppression of apoptosis in vascular endothelial cell, the promising way for natural medicines to treat atherosclerosis. Pharmacol Res 168:105599. https://doi.org/10.1016/j.phrs.2021.105599
Li MT, Ke J, Guo SF et al (2021) The protective effect of quercetin on endothelial cells injured by hypoxia and reoxygenation. Front Pharmacol 12:732874. https://doi.org/10.3389/fphar.2021.732874
Ahrens I, Peter K (2009) FX-06, a fibrin-derived Bbeta15-42 peptide for the potential treatment of reperfusion injury following myocardial infarction. Curr Opin Investig Drugs 10(9): 997–1003. https://www.ncbi.nlm.nih.gov/pubmed/19705343. Accessed 17 Aug 2023
Petzelbauer P, Zacharowski PA, Miyazaki Y et al (2005) The fibrin-derived peptide Bbeta15-42 protects the myocardium against ischemia-reperfusion injury. Nat Med 11(3):298–304. https://doi.org/10.1038/nm1198
Kim DY, Zhang H, Park S et al (2020) CU06-1004 (endothelial dysfunction blocker) ameliorates astrocyte end-feet swelling by stabilizing endothelial cell junctions in cerebral ischemia/reperfusion injury. J Mol Med (Berl) 98(6):875–886. https://doi.org/10.1007/s00109-020-01920-z
Zhang H, Park JH, Maharjan S et al (2017) Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation. J Neuroinflammation 14(1):122. https://doi.org/10.1186/s12974-017-0897-3
Noh M, Kim Y, Zhang H et al (2023) Oral administration of CU06-1004 attenuates vascular permeability and stabilizes neovascularization in retinal vascular diseases. Eur J Pharmacol 939:175427. https://doi.org/10.1016/j.ejphar.2022.175427
Park S, Oh JH, Park DJ et al (2020) CU06-1004-induced vascular normalization improves immunotherapy by modulating tumor microenvironment via cytotoxic T cells. Front Immunol 11:620166. https://doi.org/10.3389/fimmu.2020.620166
Shen J, Frye M, Lee BL et al (2014) Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest 124(10):4564–4576. https://doi.org/10.1172/JCI74527
Shi Y, Xiong Y, Lei Y et al (2019) Protective effect of COMP-angiopoietin-1 on peritoneal vascular permeability and peritoneal transport function in uremic peritoneal dialysis rats. Am J Transl Res 11(9): 5932–5943. https://www.ncbi.nlm.nih.gov/pubmed/31632561. Accessed 19 Aug 2023
Poirier B, Briand V, Kadereit D et al (2020) A G protein-biased S1P(1) agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers. Sci Signal. https://doi.org/10.1126/scisignal.aax8050
Vaidya K, Tucker B, Patel S et al (2021) Acute Coronary Syndromes (ACS)-unravelling biology to identify new therapies-the microcirculation as a frontier for new therapies in ACS. Cells. https://doi.org/10.3390/cells10092188
Matter MA, Paneni F, Libby P et al (2023) Inflammation in acute myocardial infarction: the good, the bad and the ugly. Eur Heart J. https://doi.org/10.1093/eurheartj/ehad486
Zhang Y, Wang S, Chen X et al (2022) Liraglutide prevents high glucose induced HUVECs dysfunction via inhibition of PINK1/Parkin-dependent mitophagy. Mol Cell Endocrinol 545:111560. https://doi.org/10.1016/j.mce.2022.111560
Chen Z, Wu H, Yang J et al (2022) Activating Parkin-dependent mitophagy alleviates oxidative stress, apoptosis, and promotes random-pattern skin flaps survival. Commun Biol 5(1):616. https://doi.org/10.1038/s42003-022-03556-w
Liu N, Wu J, Zhang L et al (2017) Hydrogen Sulphide modulating mitochondrial morphology to promote mitophagy in endothelial cells under high-glucose and high-palmitate. J Cell Mol Med 21(12):3190–3203. https://doi.org/10.1111/jcmm.13223
Zhou ZY, Shi WT, Zhang J et al (2023) Sodium tanshinone IIA sulfonate protects against hyperhomocysteine-induced vascular endothelial injury via activation of NNMT/SIRT1-mediated NRF2/HO-1 and AKT/MAPKs signaling in human umbilical vascular endothelial cells. Biomed Pharmacother 158:114137. https://doi.org/10.1016/j.biopha.2022.114137
Jiang T, Liu T, Deng X et al (2021) Adiponectin ameliorates lung ischemia-reperfusion injury through SIRT1-PINK1 signaling-mediated mitophagy in type 2 diabetic rats. Respir Res 22(1):258. https://doi.org/10.1186/s12931-021-01855-0
Wang X, Zhang JQ, Xiu CK et al (2020) Ginseng-Sanqi-Chuanxiong (GSC) extracts ameliorate diabetes-induced endothelial cell senescence through regulating mitophagy via the AMPK pathway. Oxid Med Cell Longev 2020:7151946. https://doi.org/10.1155/2020/7151946
Hou Y, Wang XF, Lang ZQ et al (2018) Adiponectin is protective against endoplasmic reticulum stress-induced apoptosis of endothelial cells in sepsis. Braz J Med Biol Res 51(12):e7747. https://doi.org/10.1590/1414-431X20187747
Kapadia P, Bikkina P, Landicho MA et al (2021) Effect of anti-hyperglycemic drugs on endoplasmic reticulum (ER) stress in human coronary artery endothelial cells. Eur J Pharmacol 907:174249. https://doi.org/10.1016/j.ejphar.2021.174249
Li P, Xie C, Zhong J et al (2021) Melatonin attenuates ox-LDL-induced endothelial dysfunction by reducing ER stress and inhibiting JNK/Mff SIgnaling. Oxid Med Cell Longev 2021:5589612. https://doi.org/10.1155/2021/5589612
Qi K, Li X, Geng Y et al (2018) Tongxinluo attenuates reperfusion injury in diabetic hearts by angiopoietin-like 4-mediated protection of endothelial barrier integrity via PPAR-alpha pathway. PLoS ONE 13(6):e0198403. https://doi.org/10.1371/journal.pone.0198403
Rubig E, Stypmann J, Van Slyke P et al (2016) The synthetic Tie2 agonist peptide vasculotide protects renal vascular barrier function in experimental acute kidney injury. Sci Rep 6:22111. https://doi.org/10.1038/srep22111
Shah R, Wilkins E, Nichols M et al (2019) Epidemiology report: trends in sex-specific cerebrovascular disease mortality in Europe based on WHO mortality data. Eur Heart J 40(9):755–764. https://doi.org/10.1093/eurheartj/ehy378
Collaborators GBDS (2021) Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 20(10):795–820. https://doi.org/10.1016/S1474-4422(21)00252-0
Pohl M, Hesszenberger D, Kapus K et al (2021) Ischemic stroke mimics: a comprehensive review. J Clin Neurosci 93:174–182. https://doi.org/10.1016/j.jocn.2021.09.025
Collaborators GBDCoD, (2017) Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390(10100):1151–1210. https://doi.org/10.1016/S0140-6736(17)32152-9
White BC, Sullivan JM, DeGracia DJ et al (2000) Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 179(S1–2):1–33. https://doi.org/10.1016/s0022-510x(00)00386-5
Puig B, Brenna S, Magnus T (2018) Molecular Communication of a Dying Neuron in Stroke. Int J Mol Sci. https://doi.org/10.3390/ijms19092834
Yoon JS, Jo D, Lee HS et al (2018) Spatiotemporal protein atlas of cell death-related molecules in the rat MCAO stroke model. Exp Neurobiol 27(4):287–298. https://doi.org/10.5607/en.2018.27.4.287
Pan J, Konstas AA, Bateman B et al (2007) Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology 49(2):93–102. https://doi.org/10.1007/s00234-006-0183-z
Sun MS, Jin H, Sun X et al (2018) Free radical damage in ischemia-reperfusion injury: an obstacle in acute ischemic stroke after revascularization therapy. Oxid Med Cell Longev 2018:3804979. https://doi.org/10.1155/2018/3804979
Imai T, Matsubara H, Nakamura S et al (2020) The mitochondria-targeted peptide, bendavia, attenuated ischemia/reperfusion-induced stroke damage. Neuroscience 443:110–119. https://doi.org/10.1016/j.neuroscience.2020.07.044
Yang D, Li Z, Gao G et al (2021) Combined analysis of surface protein profile and microRNA expression profile of exosomes derived from brain microvascular endothelial cells in early cerebral ischemia. ACS Omega 6(34):22410–22421. https://doi.org/10.1021/acsomega.1c03248
Hacke W, Kaste M, Bluhmki E et al (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359(13):1317–1329. https://doi.org/10.1056/NEJMoa0804656
Emberson J, Lees KR, Lyden P et al (2014) Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 384(9958):1929–1935. https://doi.org/10.1016/S0140-6736(14)60584-5
Lees KR, Emberson J, Blackwell L et al (2016) Effects of Alteplase for acute stroke on the distribution of functional outcomes: a pooled analysis of 9 trials. Stroke 47(9):2373–2379. https://doi.org/10.1161/STROKEAHA.116.013644
Goyal M, Menon BK, van Zwam WH et al (2016) Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 387(10029):1723–1731. https://doi.org/10.1016/S0140-6736(16)00163-X
Kim JS (2019) tPA helpers in the treatment of acute ischemic stroke: are they ready for clinical use? J Stroke 21(2):160–174. https://doi.org/10.5853/jos.2019.00584
Tsuji K, Aoki T, Tejima E et al (2005) Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. Stroke 36(9):1954–1959. https://doi.org/10.1161/01.STR.0000177517.01203.eb
Montaner J, Molina CA, Monasterio J et al (2003) Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107(4):598–603. https://doi.org/10.1161/01.cir.0000046451.38849.90
Mueller-Kronast NH, Zaidat OO, Froehler MT et al (2017) Systematic evaluation of patients treated with neurothrombectomy devices for acute ischemic stroke: primary results of the STRATIS Registry. Stroke 48(10):2760–2768. https://doi.org/10.1161/STROKEAHA.117.016456
Puentes S, Kurachi M, Shibasaki K et al (2012) Brain microvascular endothelial cell transplantation ameliorates ischemic white matter damage. Brain Res 1469:43–53. https://doi.org/10.1016/j.brainres.2012.06.042
Zimmet P, Alberti KG, Magliano DJ et al (2016) Diabetes mellitus statistics on prevalence and mortality: facts and fallacies. Nat Rev Endocrinol 12(10):616–622. https://doi.org/10.1038/nrendo.2016.105
Sun H, Saeedi P, Karuranga S et al (2022) IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 183:109119. https://doi.org/10.1016/j.diabres.2021.109119
Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2):88–98. https://doi.org/10.1038/nrendo.2017.151
Kocak MZ, Aktas G, Atak BM et al (2020) Is Neuregulin-4 a predictive marker of microvascular complications in type 2 diabetes mellitus? Eur J Clin Invest 50(3):e13206. https://doi.org/10.1111/eci.13206
Ozgumus T, Sulaieva O, Jessen LE et al (2021) Reduced expression of OXPHOS and DNA damage genes is linked to protection from microvascular complications in long-term type 1 diabetes: the PROLONG study. Sci Rep 11(1):20735. https://doi.org/10.1038/s41598-021-00183-z
Xue P, Covassin N, Ran X et al (2020) Association of parameters of nocturnal hypoxemia with diabetic microvascular complications: a cross-sectional study. Diabetes Res Clin Pract 170:108484. https://doi.org/10.1016/j.diabres.2020.108484
Vincent AM, Callaghan BC, Smith AL et al (2011) Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 7(10):573–583. https://doi.org/10.1038/nrneurol.2011.137
Imamura Y, Suzuki K, Saijo H et al (2022) Longitudinal physiological remoulding of lower limb skin as a cause of diabetic foot ulcer: a histopathological examination. J Wound Care 31(Sup8):S29–S35. https://doi.org/10.12968/jowc.2022.31.Sup8.S29
Yang S, Ma C, Wu H et al (2020) Tectorigenin attenuates diabetic nephropathy by improving vascular endothelium dysfunction through activating AdipoR1/2 pathway. Pharmacol Res 153:104678. https://doi.org/10.1016/j.phrs.2020.104678
Zhang Z, Yang Z, Zhu B et al (2012) Increasing glucose 6-phosphate dehydrogenase activity restores redox balance in vascular endothelial cells exposed to high glucose. PLoS ONE 7(11):e49128. https://doi.org/10.1371/journal.pone.0049128
Toth E, Racz A, Toth J et al (2007) Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH(2)/TXA(2) mediation. Am J Physiol Heart Circ Physiol 293(5):H3096-3104. https://doi.org/10.1152/ajpheart.01335.2006
Kielbik M, Szulc-Kielbik I, Klink M (2019) The potential role of iNOS in ovarian cancer progression and chemoresistance. Int J Mol Sci. https://doi.org/10.3390/ijms20071751
Pei H, Yang Y, Cui L et al (2016) Bisdemethoxycurcumin inhibits ovarian cancer via reducing oxidative stress mediated MMPs expressions. Sci Rep 6:28773. https://doi.org/10.1038/srep28773
Lv H, Cheng Q, Li Y et al (2021) The protective effects of ropivacaine against high glucose-induced brain microvascular endothelial injury by reducing mmps and alleviating oxidative stress. Neurotox Res 39(3):851–859. https://doi.org/10.1007/s12640-020-00324-8
Molitoris BA (2014) Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J Clin Invest 124(6):2355–2363. https://doi.org/10.1172/JCI72269
Yang B, Lan S, Dieude M et al (2018) Caspase-3 is a pivotal regulator of microvascular rarefaction and renal fibrosis after ischemia-reperfusion injury. J Am Soc Nephrol 29(7):1900–1916. https://doi.org/10.1681/ASN.2017050581
Doreille A, Dieude M, Cardinal H (2019) The determinants, biomarkers, and consequences of microvascular injury in kidney transplant recipients. Am J Physiol Renal Physiol 316(1):F9–F19. https://doi.org/10.1152/ajprenal.00163.2018
Babickova J, Klinkhammer BM, Buhl EM et al (2017) Regardless of etiology, progressive renal disease causes ultrastructural and functional alterations of peritubular capillaries. Kidney Int 91(1):70–85. https://doi.org/10.1016/j.kint.2016.07.038
Farris AB, Taheri D, Kawai T et al (2011) Acute renal endothelial injury during marrow recovery in a cohort of combined kidney and bone marrow allografts. Am J Transplant 11(7):1464–1477. https://doi.org/10.1111/j.1600-6143.2011.03572.x
Furuichi K, Wada T, Kaneko S et al (2008) Roles of chemokines in renal ischemia/reperfusion injury. Front Biosci 13:4021–4028. https://doi.org/10.2741/2990
Higgins DF, Kimura K, Bernhardt WM et al (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117(12):3810–3820. https://doi.org/10.1172/JCI30487
Camacho X, Nedkoff L, Wright FL et al (2022) Relative contribution of trends in myocardial infarction event rates and case fatality to declines in mortality: an international comparative study of 1.95 million events in 80.4 million people in four countries. Lancet Public Health 7(3):e229–e239. https://doi.org/10.1016/S2468-2667(22)00006-8
Frantz S, Hundertmark MJ, Schulz-Menger J et al (2022) Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies. Eur Heart J 43(27):2549–2561. https://doi.org/10.1093/eurheartj/ehac223
Zhou H, Wang S, Zhu P et al (2018) Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol 15:335–346. https://doi.org/10.1016/j.redox.2017.12.019
Tan Y, Mui D, Toan S et al (2020) SERCA overexpression improves mitochondrial quality control and attenuates cardiac microvascular ischemia-reperfusion injury. Mol Ther Nucleic Acids 22:696–707. https://doi.org/10.1016/j.omtn.2020.09.013
Funding
This work was supported by grants of the Natural Science Foundation of China (No. U1903212, 81870272), opening project of the Xinjiang Key Laboratory (2021D04020), the State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asia High Incidence Diseases fund (SKL-HIDCA-2021-XXG1, SKL-HIDCA-2022-XXG1) and the key project of the Natural Science Foundation of Xinjiang Uygur Autonomous Region (2023).
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BHZ, AR, LZ and QLL drafted the manuscript, JT, NX and AXD generated the images, MTG and XFS edited the manuscript and XMG revised the manuscript and responsible for funding support. All of the authors have read and approved the content of the manuscript.
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Zhao, BH., Ruze, A., Zhao, L. et al. The role and mechanisms of microvascular damage in the ischemic myocardium. Cell. Mol. Life Sci. 80, 341 (2023). https://doi.org/10.1007/s00018-023-04998-z
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DOI: https://doi.org/10.1007/s00018-023-04998-z