Basic Research in Cardiology

, 114:39 | Cite as

Cardioprotection of post-ischemic moderate ROS against ischemia/reperfusion via STAT3-induced the inhibition of MCU opening

  • Lan Wu
  • Ji-Liang Tan
  • Zhong-Yan Chen
  • Gang HuangEmail author
Original Contribution


Enhanced reactive oxygen species (ROS) at the beginning of reperfusion activated signal transducer and activator of transcription 3 (STAT3) in intermittent hypobaric hypoxia (IHH)-afforded cardioprotection against ischemia/reperfusion (I/R). However, its mechanism remains largely unknown. This study aimed to investigate the role and the downstream of STAT3 in exogenous enhanced post-ischemic ROS-induced cardioprotection using the model of moderate hydrogen peroxide postconditioning (H2O2PoC) mimicking endogenous ROS in IHH. Moderate H2O2PoC not only improved the post-ischemic myocardial contractile recovery and reduced the infarct size in isolated rat I/R hearts, but also alleviated mitochondrial calcium overload and ameliorated Ca2+ transients, cell contraction, and mitochondrial membrane potential in rat I/R cardiomyocytes. However, the cardioprotective effects of moderate H2O2PoC were abrogated by Janus kinase 2 (JAK2)/STAT3 inhibitor AG490 in rat hearts as well as adenovirus-delivered short hairpin RNA specific for STAT3 and the opener of mitochondrial calcium uniporter (MCU) spermine in rat cardiomyocytes. Notably, the moderate H2O2PoC-afforded cardioprotection abrogated by spermine could be rescued by STAT3 over-expression with adenovirus in rat I/R cardiomyocytes. Besides, moderate H2O2PoC enhanced mitochondrial STAT3 expression during I/R. A co-localization/interaction of STAT3 or phospho-STAT3ser727 and MCU was observed in rat cardiomyocytes with moderate H2O2PoC at 5 and 30 min of reperfusion but not in rat I/R cardiomyocytes. Further, STAT3 interacted with the N-terminal domain (NTD) of MCU in rat cardiomyocytes with moderate H2O2PoC. These findings indicated that post-ischemic moderate ROS activate STAT3 against cardiac I/R by inhibiting MCU opening via its interaction with the NTD of MCU to alleviate mitochondrial calcium overload.


Post-ischemic moderate ROS Hydrogen peroxide postconditioning Mitochondrial Ca2+ concentration Cardiac contraction Signal transducer and activator of transcription 3 Mitochondrial calcium uniporter 



This work was supported by National Natural Sciences Foundation of China (81600246), Shanghai Excellent Young Teachers Funding Project (zzjkyx16004) and Shanghai Municipal Education Commission (Plateau Disciplinary Program for Medical Technology of SUMHS, 2018-2020).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.

Supplementary material

395_2019_747_MOESM1_ESM.pdf (1.3 mb)
Supplementary material 1 (PDF 1341 kb)


  1. 1.
    Abdallah Y, Kasseckert SA, Iraqi W, Said M, Shahzad T, Erdogan A, Neuhof C, Gunduz D, Schluter KD, Tillmanns H, Piper HM, Reusch HP, Ladilov Y (2011) Interplay between Ca2+ cycling and mitochondrial permeability transition pores promotes reperfusion-induced injury of cardiac myocytes. J Cell Mol Med 15:2478–2485. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Barger SW, Hörster D, Furukawa K, Goodman Y, Krieglstein J, Mattson MP (1995) Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 92:9328–9332CrossRefGoogle Scholar
  3. 3.
    Barry SP, Townsend PA, Latchman DS, Stephanou A (2007) Role of the JAK-STAT pathway in myocardial injury. Trends Mol Med 13:82–89. CrossRefPubMedGoogle Scholar
  4. 4.
    Becker LB (2004) New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res 61:461–470. CrossRefPubMedGoogle Scholar
  5. 5.
    Boengler K, Buechert A, HeinenY Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R (2008) Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 102:131–135. CrossRefPubMedGoogle Scholar
  6. 6.
    Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R (2010) Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res Cardiol 105:771–785. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Boengler K, Lochnit G, Schulz R (2018) Mitochondria “THE” target of myocardial conditioning. Am J Physiol Heart Circ Physiol 315:H1215–H1231. CrossRefPubMedGoogle Scholar
  8. 8.
    Bøtker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femminò S, García-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhäuser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schlüter 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. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287:C817–833. CrossRefPubMedGoogle Scholar
  10. 10.
    Cao CM, Yan WY, Liu J, Kam KW, Zhan SZ, Sham JS, Wong TM (2006) Attenuation of mitochondrial, but not cytosolic, Ca2+ overload reduces myocardial injury induced by ischemia and reperfusion. Acta Pharmacol Sin 27:911–918. CrossRefPubMedGoogle Scholar
  11. 11.
    Chen L, Lu XY, Li J, Fu JD, Zhou ZN, Yang HT (2006) Intermittent hypoxia protects cardiomyocytes against ischemia-reperfusion injury-induced alterations in Ca2+ homeostasis and contraction via the sarcoplasmic reticulum and Na+/Ca2+ exchange mechanisms. Am J Physiol Cell Physiol 290:C1221–1229. CrossRefPubMedGoogle Scholar
  12. 12.
    Chen YX, Liu JL, Zheng YJ, Wang JX, Wang ZH, Gu SS, Tan JL, Jing Q, Yang HT (2015) Uncoupling protein 3 mediates H2O2 preconditioning-afforded cardioprotection through the inhibition of MPTP opening. Cardiovasc Res 105:192–202. CrossRefPubMedGoogle Scholar
  13. 13.
    de Jesus Garcia-Rivas G, Guerrero-Hernandez A, Guerrero-Serna G, Rodriguez-Zavala JS, Zazueta C (2005) Inhibition of the mitochondrial calcium uniporter by the oxo-bridged dinuclear ruthenium amine complex (Ru360) prevents from irreversible injury in postischemic rat heart. FEBS J 272:3477–3488. CrossRefPubMedGoogle Scholar
  14. 14.
    Finkel T, Menazza S, Holmstrom KM, Parks RJ, Liu J, Sun J, Liu J, Pan X, Murphy E (2015) The ins and outs of mitochondrial calcium. Circ Res 116:1810–1819. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gao H, Chen L, Yang HT (2007) Activation of alpha1B-adrenoceptors alleviates ischemia/reperfusion injury by limitation of mitochondrial Ca2+ overload in cardiomyocytes. Cardiovasc Res 75:584–595. CrossRefPubMedGoogle Scholar
  16. 16.
    Gao Q, Zhang SZ, Mao HH, Li QS, Cao CM, Xia Q (2006) Mitochondrial calcium uniporter participates in TNF-alpha induced cardioprotection in isolated rat hearts subjected to ischemia/reperfusion. Zhongguo Ying Yong Sheng Li Xue Za Zhi 22:278–282PubMedGoogle Scholar
  17. 17.
    Gedik N, Maciel L, Schulte C, Skyschally A, Heusch G, Kleinbongard P (2017) Cardiomyocyte mitochondria as targets of humoral factors released by remote ischemic preconditioning. Arch Med Sci. 13:448–458. CrossRefPubMedGoogle Scholar
  18. 18.
    Hattori R, Maulik N, Otani H, Zhu L, Cordis G, Engelman RM, Siddiqui MA, Das DK (2001) Role of STAT3 in ischemic preconditioning. J Mol Cell Cardiol 33:1929–1936. CrossRefPubMedGoogle Scholar
  19. 19.
    Hauerslev M, Mørk SR, Pryds K, Contractor H, Hansen J, Jespersen NR, Johnsen J, Heusch G, Kleinbongard P, Kharbanda R, Bøtker HE, Schmidt MR (2018) Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning. Am J Physiol Heart Circ Physiol 315:H150–H158. CrossRefPubMedGoogle Scholar
  20. 20.
    Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. CrossRefPubMedGoogle Scholar
  21. 21.
    Heusch G (2017) Cardioprotection is alive but remains enigmatic: the nitric oxide-protein kinases-mitochondria signaling axis. Circulation 136:2356–2358. CrossRefPubMedGoogle Scholar
  22. 22.
    Heusch G, Musiolik J, Gedik N, Skyschally A (2011) Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 109:1302–1308. CrossRefPubMedGoogle Scholar
  23. 23.
    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 122:1102–1108CrossRefGoogle Scholar
  24. 24.
    Klinbongard P, Gedik N, Kirca M, Stoian L, Frey U, Zandi A, Thielmann M, Jakob H, Peters J, Kamler M, Heusch G (2018) Mitochondrial and contractile function of human right atrial tissue in response to remote ischemic conditioning. J Am Heart Assoc 7:e009540. CrossRefGoogle Scholar
  25. 25.
    Kleinbongard P, Skyschally A, Gent S, Pesch M, Heusch G (2017) STAT3 as a common signal of ischemic conditioning: a lesson on “rigor and reproducibility” in preclinical studies on cardioprotection. Basic Res Cardiol. 113:3. CrossRefPubMedGoogle Scholar
  26. 26.
    Kleinbongard P, Skyschally A, Heusch G (2017) Cardioprotection by remote ischemic conditioning and its signal transduction. Pflug Arch 469:159–181. CrossRefGoogle Scholar
  27. 27.
    Kwong JQ, Lu X, Correll RN, Schwanekamp JA, Vagnozzi RJ, Sargent MA, York AJ, Zhang J, Bers DM, Molkentin JD (2015) The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Rep 12:15–22. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lacerda L, Somers S, Opie LH, Lecour S (2009) Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res 84:201–208. CrossRefPubMedGoogle Scholar
  29. 29.
    Lecour S, Suleman N, Deuchar GA, Somers S, Lacerda L, Huisamen B, Opie LH (2005) Pharmacological preconditioning with tumor necrosis factor-alpha activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (AKT and extracellular signal-regulated kinase). Circulation 112:3911–3918. CrossRefPubMedGoogle Scholar
  30. 30.
    Lee Y, Min CK, Kim TG, Song HK, Lim Y, Kim D, Shin K, Kang M, Kang JY, Youn HS, Lee JG, An JY, Park KR, Lim JJ, Kim JH, Kim JH, Park ZY, Kim YS, Wang J, Kim DH, Eom SH (2015) Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter. EMBO Rep 16:1318–1333. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lu XY, Chen L, Cai XL, Yang HT (2008) Overexpression of heat shock protein 27 protects against ischaemia/reperfusion-induced cardiac dysfunction via stabilization of troponin I and T. Cardiovasc Res 79:500–508. CrossRefPubMedGoogle Scholar
  33. 33.
    Mallet RT, Manukhina EB, Ruelas SS, Caffrey JL, Downey HF (2018) Cardioprotection by intermittent hypoxia conditioning: evidence, mechanisms, and therapeutic potential. Am J Physiol Heart Circ Physiol 315:H216–H232. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Martell JD, Deerinck TJ, Sancak Y, Poulos TL, Mootha VK, Sosinsky GE, Ellisman MH, Ting AY (2012) Engineered ascorbate peroxidase as a genetically encoded reporter for electron microscopy. Nat Biotechnol 30:1143–1148. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    McAllister SE, Ashrafpour H, Cahoon N, Huang N, Moses MA, Neligan PC, Forrest CR, Lipa JE, Pang CY (2008) Postconditioning for salvage of ischemic skeletal muscle from reperfusion injury: efficacy and mechanism. Am J Physiol Regul Integr Comp Physiol 295:R681–689. CrossRefPubMedGoogle Scholar
  36. 36.
    Michels G, Khan IF, Endres-Becker J, Rottlaender D, Herzig S, Ruhparwar A, Wahlers T, Hoppe UC (2009) Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation 119:2435–2443. CrossRefPubMedGoogle Scholar
  37. 37.
    Miyawaki H, Wang Y, Ashraf M (1998) Oxidant stress with hydrogen peroxide attenuates calcium paradox injury: role of protein kinase C and ATP-sensitive potassium channel. Cardiovasc Res 37:691–699CrossRefGoogle Scholar
  38. 38.
    Motloch LJ, Reda S, Wolny M, Hoppe UC (2015) UCP2 modulates cardioprotective effects of Ru360 in isolated cardiomyocytes during ischemia. Pharmaceuticals (Basel) 8:474–482. CrossRefGoogle Scholar
  39. 39.
    Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI, Eizirik DL, Osugi T, Izumi M, Oshima Y, Nakaoka Y, Hirota H, Kishimoto T, Yamauchi-Takihara K (2001) Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 104:979–981CrossRefGoogle Scholar
  40. 40.
    Oropeza-Almazan Y, Vazquez-Garza E, Chapoy-Villanueva H, Torre-Amione G, Garcia-Rivas G (2017) Small interfering RNA targeting mitochondrial calcium uniporter improves cardiomyocyte cell viability in hypoxia/reoxygenation injury by reducing calcium overload. Oxid Med Cell Longev 2017:5750897. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Oshima Y, Fujio Y, Nakanishi T, Itoh N, Yamamoto Y, Negoro S, Tanaka K, Kishimoto T, Kawase I, Azuma J (2005) STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart. Cardiovasc Res 65:428–435. CrossRefPubMedGoogle Scholar
  42. 42.
    Penna C, Mancardi D, Rastaldo R, Pagliaro P (2009) Cardioprotection: a radical view Free radicals in pre and postconditioning. Biochim Biophys Acta 1787:781–793. CrossRefPubMedGoogle Scholar
  43. 43.
    Pierrat B, Ito M, Hinz W, Simonen M, Erdmann D, Chiesi M, Heim J (2000) Uncoupling proteins 2 and 3 interact with members of the 14.3.3 family. Eur J Biochem 267:2680–2687CrossRefGoogle Scholar
  44. 44.
    Piper HM, Meuter K, Schäfer C (2003) Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg 75:S644–648CrossRefGoogle Scholar
  45. 45.
    Rasmussen TP, Wu Y, Joiner ML, Koval OM, Wilson NR, Luczak ED, Wang Q, Chen B, Gao Z, Zhu Z, Wagner BA, Soto J, McCormick ML, Kutschke W, Weiss RM, Yu L, Boudreau RL, Abel ED, Zhan F, Spitz DR, Buettner GR, Song LS, Zingman LV, Anderson ME (2015) Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proc Natl Acad Sci USA 112:9129–9134. CrossRefPubMedGoogle Scholar
  46. 46.
    Sharikabad MN, Ostbye KM, Brors O (2004) Effect of hydrogen peroxide on reoxygenation-induced Ca2+ accumulation in rat cardiomyocytes. Free Radic Biol Med 37:531–538. CrossRefPubMedGoogle Scholar
  47. 47.
    Skyschally A, Kleinbongard P, Lieder H, Gedik N, Stoian L, Amanakis G, Elbers E, Heusch G (2018) Humoral transfer and intramyocardial signal transduction of protection by remote ischemic perconditioning in pigs, rats, and mice. Am J Physiol Heart Circ Physiol. 315:H159–H172. CrossRefPubMedGoogle Scholar
  48. 48.
    Smith CC, Dixon RA, Wynne AM, Theodorou L, Ong SG, Subrayan S, Davidson SM, Hausenloy DJ, Yellon DM (2010) Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol 299:1265–1270. CrossRefGoogle Scholar
  49. 49.
    Sucher R, Gehwolf P, Kaier T, Hermann M, Maglione M, Oberhuber R, Ratschiller T, Kuznetsov AV, Bosch F, Kozlov AV, Ashraf MI, Schneeberger S, Brandacher G, Ollinger R, Margreiter R, Troppmair J (2009) Intracellular signaling pathways control mitochondrial events associated with the development of ischemia/reperfusion-associated damage. Transpl Int 22:922–930. CrossRefPubMedGoogle Scholar
  50. 50.
    Sun Y, Deng T, Lu N, Yan M, Zheng X (2010) B-type natriuretic peptide protects cardiomyocytes at reperfusion via mitochondrial calcium uniporter. Biomed Pharmacother 64:170–176. CrossRefPubMedGoogle Scholar
  51. 51.
    Szczepanek K, Xu A, Hu Y, Thompson J, He J, Larner AC, Salloum FN, Chen Q, Lesnefsky EJ (2015) Cardioprotective function of mitochondrial-targeted and transcriptionally inactive STAT3 against ischemia and reperfusion injury. Basic Res Cardiol 110:53–63. CrossRefPubMedGoogle Scholar
  52. 52.
    Wang ZH, Chen YX, Zhang CM, Wu L, Yu Z, Cai XL, Guan Y, Zhou ZN, Yang HT (2011) Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion. Am J Physiol Heart Circ Physiol 301:1695–1705. CrossRefGoogle Scholar
  53. 53.
    Wang ZH, Liu JL, Wu L, Yu Z, Yang HT (2014) Concentration-dependent wrestling between detrimental and protective effects of H2O2 during myocardial ischemia/reperfusion. Cell Death Dis 5:e1297. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY, Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC (2009) Function of mitochondrial STAT3 in cellular respiration. Science 323:793–797. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wu L, Tan JL, Wang ZH, Chen YX, Gao L, Liu JL, Shi YH, Endoh M, Yang HT (2015) ROS generated during early reperfusion contribute to intermittent hypobaric hypoxia-afforded cardioprotection against postischemia-induced Ca2+ overload and contractile dysfunction via the JAK2/STAT3 pathway. J Mol Cell Cardiol 81:150–161. CrossRefPubMedGoogle Scholar
  56. 56.
    Yamanaka K, Eldeiry M, Aftab M, Ryan TJ, Roda G, Meng X, Weyant MJ, Cleveland JC Jr, Fullerton DA, Reece TB (2019) Pretreatment with diazoxide attenuates spinal cord ischemia-reperfusion injury through signaling transducer and activator of transcription 3 pathway. Ann Thorac Surg 107:733–739. CrossRefPubMedGoogle Scholar
  57. 57.
    Yu TN, Hong H, Yang JQ, Gao Q, Xia Q (2011) Role of mitochondrial calcium uniporter in cardioprotection induced by ischemic postconditioning in isolated rat heart. Zhejiang Da Xue Xue Bao Yi Xue Ban 40:304–308PubMedGoogle Scholar
  58. 58.
    Zhang L, Wang S, Dong H, Li Y, Wang P, Li S, Guo Y, Yao R (2014) Spermine attenuates the preconditioning of diazoxide against transient focal cerebral ischemia in rats. Neurol Res 36:666–672. CrossRefPubMedGoogle Scholar
  59. 59.
    Zhang J, Chen FJ, Li WL, Xiong Q, Yang MK, Zheng P, Li CY, Pei JF, Ge F (2012) 14-3-3zeta interacts with STAT3 and regulates its constitutive activation in multiple myeloma cells. PLoS One 7:e29554. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Zhang SZ, Gao Q, Cao CM, Bruce IC, Xia Q (2006) Involvement of the mitochondrial calcium uniporter in cardioprotection by ischemic preconditioning. Life Sci 78:738–745. CrossRefPubMedGoogle Scholar
  61. 61.
    Zhu WZ, Xie Y, Chen L, Yang HT, Zhou ZN (2006) Intermittent high altitude hypoxia inhibits opening of mitochondrial permeability transition pores against reperfusion injury. J Mol Cell Cardiol 40:96–106. CrossRefGoogle Scholar

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

Authors and Affiliations

  1. 1.School of Basic Medical Sciences and Shanghai Key Laboratory of Molecular ImagingShanghai University of Medicine and Health SciencesShanghaiChina
  2. 2.Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and HealthShanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS)ShanghaiChina
  3. 3.Department of CardiologyShanghai University of Medicine and Health Sciences Affiliated Zhoupu HospitalShanghaiChina

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