Advertisement

Molecular pathways involved in the cardioprotective effects of intravenous statin administration during ischemia

  • Guiomar Mendieta
  • Soumaya Ben-Aicha
  • Laura Casani
  • Lina Badimon
  • Manel Sabate
  • Gemma VilahurEmail author
Original Contribution
  • 113 Downloads

Abstract

The success of therapies targeting myocardial reperfusion injury is limited, while the cardioprotective impact of mitigating ischemia-related damage remains less explored. We have recently shown in a pig model that the intravenous administration of a modified atorvastatin preparation during ischemia attenuates the rise of cardiac ischemia injury biomarkers. In the following study, we sought to investigate the mechanisms behind these ischemia-related cardioprotective effects. Ischemia was induced by 90 min total coronary balloon occlusion in pigs fed a normocholesterolemic regime. Fifteen minutes after the onset of ischemia, animals were randomized to receive intravenous atorvastatin preparation (IV-atorva) or vehicle. After ischemia animals were euthanized to assess the effect of IV-atorva treatment on gene and protein levels/activation of senescence-, apoptosis-, and cardioprotective/metabolic-related markers. Proof-of-concept studies were carried out in mice and rats in which treatments or vehicle were administered 15 min after initiation of ischemia induced by permanent coronary ligation. Western-blot analyses revealed that in the ischemic myocardium of IV-atorva-treated pigs, RhoA was inactivated, phosphorylation of p53 and caspase-3 was reduced and AMPK was activated with the consequent regulation of the mTOR/raptor-signaling pathway. IV-atorva-treated rats showed, as compared to vehicle, a significant reduction (60%) in scar size assessed at 1 month by histological staining, and mice studies demonstrated the causal involvement of AMPK activation in IV-atorva mediated cardioprotective effects. We demonstrate in pigs and rodents that prompt intravenous treatment with atorvastatin during ischemia limits cardiac cell death and reduces infarct size through AMPK signaling.

Keywords

Myocardial ischemia Intravenous statin Cardioprotection Animal models AMPK 

Notes

Acknowledgements

We gratefully acknowledge the valuable help and support of M.A. Canovas, P. Catalina, and J. Moreno with animal handling and for the proper conduct of all the experimental and molecular work. This article is part of the PhD studies of G.Mendieta at the Medical School of the University of Barcelona and at the Cardiovascular Program ICCC.

Funding

This work was supported by the Fundació Investigació Marato TV3 #20154310 (to GV), Plan Nacional de Salud (PNS) [PGC2018-094025-B-I00 to GV and SAF2016-76819-R to LB] from the Spanish Ministry of Science and Innovation and funds FEDER “Una Manera de Hacer Europa”; and CIBERCV (to LB). We thank the support of the Generalitat of Catalunya (Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat, 2017 SGR 1480) and the Fundación Investigación Cardiovascular-Fundación Jesus Serra for their continuous support.

Compliance with ethical standards

Conflict of interest

LB and GV are the authors of the patent (PCT/EP2018/058158) that includes the use of statins for intravenous administration. The remaining authors have no conflict of interest.

Supplementary material

395_2019_760_MOESM1_ESM.tif (295 kb)
Supplementary material 1 (TIFF 294 kb)
395_2019_760_MOESM2_ESM.tif (139 kb)
Supplementary material 2 (TIFF 138 kb)

References

  1. 1.
    Antoniades C, Demosthenous M, Reilly S, Margaritis M, Zhang MH, Antonopoulos A, Marinou K, Nahar K, Jayaram R, Tousoulis D, Bakogiannis C, Sayeed R, Triantafyllou C, Koumallos N, Psarros C, Miliou A, Stefanadis C, Channon KM, Casadei B (2012) Myocardial redox state predicts in-hospital clinical outcome after cardiac surgery effects of short-term pre-operative statin treatment. J Am Coll Cardiol 59:60–70.  https://doi.org/10.1016/j.jacc.2011.08.062 CrossRefPubMedGoogle Scholar
  2. 2.
    Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376:1670–1681.  https://doi.org/10.1016/S0140-6736(10)61350-5 CrossRefPubMedGoogle Scholar
  3. 3.
    Bell RM, Yellon DM (2003) Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway. J Am Coll Cardiol 41:508–515.  https://doi.org/10.1016/s0735-1097(02)02816-4 CrossRefPubMedGoogle Scholar
  4. 4.
    Berwanger O, Santucci EV, de Barros ESPGM, Jesuino IA, Damiani LP, Barbosa LM, Santos RHN, Laranjeira LN, Egydio FM, Borges de Oliveira JA, Dall Orto FTC, Beraldo de Andrade P, Bienert IRC, Bosso CE, Mangione JA, Polanczyk CA, Sousa A, Kalil RAK, Santos LM, Sposito AC, Rech RL, Sousa ACS, Baldissera F, Nascimento BR, Giraldez R, Cavalcanti AB, Pereira SB, Mattos LA, Armaganijan LV, Guimaraes HP, Sousa J, Alexander JH, Granger CB, Lopes RD, Investigators S-P (2018) Effect of loading dose of atorvastatin prior to planned percutaneous coronary intervention on major adverse cardiovascular events in acute coronary syndrome: the SECURE-PCI randomized clinical trial. JAMA 319:1331–1340.  https://doi.org/10.1001/jama.2018.2444 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Botker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femmino S, Garcia-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhauser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schluter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39.  https://doi.org/10.1007/s00395-018-0696-8 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Braunwald E, Kloner RA (1985) Myocardial reperfusion: a double-edged sword? J Clin Investig 76:1713–1719.  https://doi.org/10.1172/JCI112160 CrossRefPubMedGoogle Scholar
  7. 7.
    Bulhak A, Roy J, Hedin U, Sjoquist PO, Pernow J (2007) Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation. Am J Physiol-Heart Circ Physiol 292:H3158–H3163.  https://doi.org/10.1152/ajpheart.01354.2006 CrossRefPubMedGoogle Scholar
  8. 8.
    Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM, Pravastatin or Atorvastatin E, Infection Therapy-Thrombolysis in Myocardial Infarction I (2004) Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495–1504.  https://doi.org/10.1056/NEJMoa040583 CrossRefPubMedGoogle Scholar
  9. 9.
    Cubedo J, Vilahur G, Casani L, Mendieta G, Gomez-Jabalera E, Juan-Babot O, Padro T, Badimon L (2016) Targeting the molecular mechanisms of ischemic damage: protective effects of alpha-crystallin-B. Int J Cardiol 215:406–416.  https://doi.org/10.1016/j.ijcard.2016.04.072 CrossRefPubMedGoogle Scholar
  10. 10.
    Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guerin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Rande JL, Unterseeh T, Le Breton H, Beard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M (2015) Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 373:1021–1031.  https://doi.org/10.1056/NEJMoa1505489 CrossRefPubMedGoogle Scholar
  11. 11.
    Davidson SM, Ferdinandy P, Andreadou I, Botker HE, Heusch G, Ibanez B, Ovize M, Schulz R, Yellon DM, Hausenloy DJ, Garcia-Dorado D, Action CC (2019) Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. J Am Coll Cardiol 73:89–99.  https://doi.org/10.1016/j.jacc.2018.09.086 CrossRefPubMedGoogle Scholar
  12. 12.
    de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E, Investigators (2004) Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 292:1307–1316.  https://doi.org/10.1001/jama.292.11.1307 CrossRefPubMedGoogle Scholar
  13. 13.
    Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A (2009) Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (atorvastatin for reduction of myocardial damage during angioplasty) randomized trial. J Am Coll Cardiol 54:558–565.  https://doi.org/10.1016/j.jacc.2009.05.028 CrossRefPubMedGoogle Scholar
  14. 14.
    Duran X, Vilahur G, Badimon L (2009) Exogenous in vivo NO-donor treatment preserves p53 levels and protects vascular cells from apoptosis. Atherosclerosis 205:101–106.  https://doi.org/10.1016/j.atherosclerosis.2008.11.016 CrossRefPubMedGoogle Scholar
  15. 15.
    Garcia-Ruiz JM, Fernandez-Jimenez R, Garcia-Alvarez A, Pizarro G, Galan-Arriola C, Fernandez-Friera L, Mateos A, Nuno-Ayala M, Aguero J, Sanchez-Gonzalez J, Garcia-Prieto J, Lopez-Melgar B, Martinez-Tenorio P, Lopez-Martin GJ, Macias A, Perez-Asenjo B, Cabrera JA, Fernandez-Ortiz A, Fuster V, Ibanez B (2016) Impact of the timing of metoprolol administration during STEMI on infarct size and ventricular function. J Am Coll Cardiol 67:2093–2104.  https://doi.org/10.1016/j.jacc.2016.02.050 CrossRefPubMedGoogle Scholar
  16. 16.
    Gaspar A, Lourenco AP, Pereira MA, Azevedo P, Roncon-Albuquerque R Jr, Marques J, Leite-Moreira AF (2018) Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI). Basic Res Cardiol 113:14.  https://doi.org/10.1007/s00395-018-0672-3 CrossRefGoogle Scholar
  17. 17.
    Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226.  https://doi.org/10.1016/j.molcel.2008.03.003 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Herrmann J, Lerman A, Baumgart D, Volbracht L, Schulz R, von Birgelen C, Haude M, Heusch G, Erbel R (2002) Preprocedural statin medication reduces the extent of periprocedural non-Q-wave myocardial infarction. Circulation 106:2180–2183.  https://doi.org/10.1161/01.cir.0000037520.89770.5e CrossRefPubMedGoogle Scholar
  19. 19.
    Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699.  https://doi.org/10.1161/circresaha.116.305348 CrossRefPubMedGoogle Scholar
  20. 20.
    Heusch G, Skyschally A, Kleinbongard P (2018) Translation, translation, translation. Circ Res 123:931–933.  https://doi.org/10.1161/circresaha.118.313947 CrossRefPubMedGoogle Scholar
  21. 21.
    Ibanez B, Heusch G, Ovize M, Van de Werf F (2015) Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 65:1454–1471.  https://doi.org/10.1016/j.jacc.2015.02.032 CrossRefPubMedGoogle Scholar
  22. 22.
    Johansson S, Rosengren A, Young K, Jennings E (2017) Mortality and morbidity trends after the first year in survivors of acute myocardial infarction: a systematic review. BMC Cardiovasc Disord 17:53.  https://doi.org/10.1186/s12872-017-0482-9 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kamel WA, Sugihara E, Nobusue H, Yamaguchi-Iwai S, Onishi N, Maki K, Fukuchi Y, Matsuo K, Muto A, Saya H, Shimizu T (2017) Simvastatin-induced apoptosis in osteosarcoma cells: a key role of RhoA-AMPK/p38 MAPK signaling in antitumor activity. Mol Cancer Ther 16:182–192.  https://doi.org/10.1158/1535-7163.MCT-16-0499 CrossRefPubMedGoogle Scholar
  24. 24.
    Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412.  https://doi.org/10.1371/journal.pbio.1000412 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kinlay S, Schwartz GG, Olsson AG, Rifai N, Sasiela WJ, Szarek M, Ganz P, Libby P, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study I (2004) Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study. Circulation 110:386–391.  https://doi.org/10.1161/01.cir.0000136588.62638.5e CrossRefPubMedGoogle Scholar
  26. 26.
    Kleinbongard P, Amanakis G, Skyschally A, Heusch G (2018) Reflection of cardioprotection by remote ischemic perconditioning in attenuated ST-segment elevation during ongoing coronary occlusion in pigs: evidence for cardioprotection from ischemic injury. Circ Res 122:1102–1108.  https://doi.org/10.1161/CIRCRESAHA.118.312784 CrossRefGoogle Scholar
  27. 27.
    Lacerda L, Somers S, Opie LH, Lecour S (2009) Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res 84:201–208.  https://doi.org/10.1093/cvr/cvp274 CrossRefPubMedGoogle Scholar
  28. 28.
    Laufs U, Adam O (2012) Acute effects of statins. J Am Coll Cardiol 59:71–73.  https://doi.org/10.1016/j.jacc.2011.08.063 CrossRefPubMedGoogle Scholar
  29. 29.
    Lindsey ML, Bolli R, Canty JM Jr, Du XJ, Frangogiannis NG, Frantz S, Gourdie RG, Holmes JW, Jones SP, Kloner RA, Lefer DJ, Liao R, Murphy E, Ping P, Przyklenk K, Recchia FA, Schwartz Longacre L, Ripplinger CM, Van Eyk JE, Heusch G (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812–H838.  https://doi.org/10.1152/ajpheart.00335.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ludolph B, Bloch W, Kelm M, Schulz R, Kleinbongard P (2007) Short-term effect of the HMG-CoA reductase inhibitor rosuvastatin on erythrocyte nitric oxide synthase activity. Vasc Health Risk Manag 3:1069–1073PubMedPubMedCentralGoogle Scholar
  31. 31.
    Mendieta G, Ben-Aicha S, Casani L, Badimon L, Sabate M, Vilahur G (2019) Intravenous statin administration during ischemia exerts cardioprotective effects. J Am Coll Cardiol 74:475–477.  https://doi.org/10.1016/j.jacc.2019.05.020 CrossRefPubMedGoogle Scholar
  32. 32.
    Niccoli G, Montone RA, Ibanez B, Thiele H, Crea F, Heusch G, Bulluck H, Hausenloy DJ, Berry C, Stiermaier T, Camici PG, Eitel I (2019) Optimized treatment of ST-elevation myocardial infarction. Circ Res 125:245–258.  https://doi.org/10.1161/CIRCRESAHA.119.315344 CrossRefPubMedGoogle Scholar
  33. 33.
    Nikolaou PE, Boengler K, Efentakis P, Vouvogiannopoulou K, Zoga A, Gaboriaud-Kolar N, Myrianthopoulos V, Alexakos P, Kostomitsopoulos N, Rerras I, Tsantili-Kakoulidou A, Skaltsounis AL, Papapetropoulos A, Iliodromitis EK, Schulz R, Andreadou I (2019) Investigating and re-evaluating the role of glycogen synthase kinase 3 beta kinase as a molecular target for cardioprotection by using novel pharmacological inhibitors. Cardiovasc Res 115:1228–1243.  https://doi.org/10.1093/cvr/cvz061 CrossRefPubMedGoogle Scholar
  34. 34.
    Noda K, Nakajima S, Godo S, Saito H, Ikeda S, Shimizu T, Enkhjargal B, Fukumoto Y, Tsukita S, Yamada T, Katagiri H, Shimokawa H (2014) Rho-kinase inhibition ameliorates metabolic disorders through activation of AMPK pathway in mice. PLoS One 9:e110446.  https://doi.org/10.1371/journal.pone.0110446 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Oakhill JS, Scott JW, Kemp BE (2012) AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab TEM 23:125–132.  https://doi.org/10.1016/j.tem.2011.12.006 CrossRefPubMedGoogle Scholar
  36. 36.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Group ESCSD (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur heart J 37:2129–2200.  https://doi.org/10.1093/eurheartj/ehw128 CrossRefPubMedGoogle Scholar
  37. 37.
    Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E, Pravastatin or Atorvastatin E, Infection Therapy-Thrombolysis in Myocardial Infarction I (2005) C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352:20–28.  https://doi.org/10.1056/NEJMoa042378 CrossRefPubMedGoogle Scholar
  38. 38.
    Rossello X, Ibanez B (2018) Infarct size reduction by targeting ischemic injury: back to square one. Circ Res 122:1041–1043.  https://doi.org/10.1161/circresaha.118.312939 CrossRefPubMedGoogle Scholar
  39. 39.
    Rufini A, Tucci P, Celardo I, Melino G (2013) Senescence and aging: the critical roles of p53. Oncogene 32:5129–5143.  https://doi.org/10.1038/onc.2012.640 CrossRefPubMedGoogle Scholar
  40. 40.
    Russell RR 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Investig 114:495–503.  https://doi.org/10.1172/JCI19297 CrossRefPubMedGoogle Scholar
  41. 41.
    Scalia R, Gooszen ME, Jones SP, Hoffmeyer M, Rimmer DM 3rd, Trocha SD, Huang PL, Smith MB, Lefer AM, Lefer DJ (2001) Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation 103:2598–2603.  https://doi.org/10.1161/01.cir.103.21.2598 CrossRefPubMedGoogle Scholar
  42. 42.
    Skyschally A, van Caster P, Iliodromitis EK, Schulz R, Kremastinos DT, Heusch G (2009) Ischemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol 104:469–483.  https://doi.org/10.1007/s00395-009-0040-4 CrossRefPubMedGoogle Scholar
  43. 43.
    Sun W, Lee TS, Zhu M, Gu C, Wang Y, Zhu Y, Shyy JY (2006) Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation 114:2655–2662.  https://doi.org/10.1161/circulationaha.106.630194 CrossRefPubMedGoogle Scholar
  44. 44.
    Touboul C, Angoulvant D, Mewton N, Ivanes F, Muntean D, Prunier F, Ovize M, Bejan-Angoulvant T (2015) Ischaemic postconditioning reduces infarct size: systematic review and meta-analysis of randomized controlled trials. Arch Cardiovasc Dis 108:39–49.  https://doi.org/10.1016/j.acvd.2014.08.004 CrossRefPubMedGoogle Scholar
  45. 45.
    Tsimikas S, Witztum JL, Miller ER, Sasiela WJ, Szarek M, Olsson AG, Schwartz GG, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study I (2004) High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Circulation 110:1406–1412.  https://doi.org/10.1161/01.cir.0000141728.23033.b5 CrossRefPubMedGoogle Scholar
  46. 46.
    Vilahur G, Casani L, Juan-Babot O, Guerra JM, Badimon L (2012) Infiltrated cardiac lipids impair myofibroblast-induced healing of the myocardial scar post-myocardial infarction. Atherosclerosis 224:368–376.  https://doi.org/10.1016/j.atherosclerosis.2012.07.003 CrossRefPubMedGoogle Scholar
  47. 47.
    Vilahur G, Casani L, Pena E, Duran X, Juan-Babot O, Badimon L (2009) Induction of RISK by HMG-CoA reductase inhibition affords cardioprotection after myocardial infarction. Atherosclerosis 206:95–101.  https://doi.org/10.1016/j.atherosclerosis.2009.02.009 CrossRefPubMedGoogle Scholar
  48. 48.
    Vilahur G, Casani L, Pena E, Juan-Babot O, Mendieta G, Crespo J, Badimon L (2014) HMG-CoA reductase inhibition prior reperfusion improves reparative fibrosis post-myocardial infarction in a preclinical experimental model. Int J Cardiol 175:528–538.  https://doi.org/10.1016/j.ijcard.2014.06.040 CrossRefPubMedGoogle Scholar
  49. 49.
    Vilahur G, Cubedo J, Casani L, Padro T, Sabate-Tenas M, Badimon JJ, Badimon L (2013) Reperfusion-triggered stress protein response in the myocardium is blocked by post-conditioning. Systems biology pathway analysis highlights the key role of the canonical aryl-hydrocarbon receptor pathway. Eur Heart J 34:2082–2093.  https://doi.org/10.1093/eurheartj/ehs211 CrossRefPubMedGoogle Scholar
  50. 50.
    Vilahur G, Gutierrez M, Casani L, Cubedo J, Capdevila A, Pons-Llado G, Carreras F, Hidalgo A, Badimon L (2015) Hypercholesterolemia abolishes high-density lipoprotein-related cardioprotective effects in the setting of myocardial infarction. J Am Coll Cardiol 66:2469–2470.  https://doi.org/10.1016/j.jacc.2015.08.901 CrossRefPubMedGoogle Scholar
  51. 51.
    Vilahur G, Hernandez-Vera R, Molins B, Casani L, Duran X, Padro T, Badimon L (2009) Short-term myocardial ischemia induces cardiac modified C-reactive protein expression and proinflammatory gene (cyclo-oxygenase-2, monocyte chemoattractant protein-1, and tissue factor) upregulation in peripheral blood mononuclear cells. J Thromb Haemost JTH 7:485–493.  https://doi.org/10.1111/j.1538-7836.2008.03244.x CrossRefPubMedGoogle Scholar
  52. 52.
    Vilahur G, Juan-Babot O, Pena E, Onate B, Casani L, Badimon L (2011) Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction. J Mol Cell Cardiol 50:522–533.  https://doi.org/10.1016/j.yjmcc.2010.12.021 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Cardiovascular Program-ICCCResearch Institute-Hospital de la Santa Creu i Sant Pau, IIB-Sant PauBarcelonaSpain
  2. 2.School of MedicineUniversity of Barcelona (UB)BarcelonaSpain
  3. 3.Cardiovascular InstituteHospital Clínic, IDIBAPS, University of Barcelona (UB)BarcelonaSpain
  4. 4.CIBERCV, Instituto Salud Carlos IIIMadridSpain
  5. 5.Cardiovascular Research Chair Autonomous University of Barcelona (UAB)BarcelonaSpain

Personalised recommendations