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Insulin inhibits myocardial ischemia-induced apoptosis and alleviates chronic adverse changes in post-ischemic cardiac structure and function

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Abstract

Insulin has been shown to possess significant anti-apoptotic effect in myocardial ischemia/reperfusion (MI/R). However, the contribution by this protection of insulin to the prolonged cardiac function in rats subjected to ischemia remains unclear. The present study attempted to test whether early insulin treatment influences adverse prolonged post-ischemic cardiac structural and functional changes. Adult male rats were subjected to left anterior descending coronary artery occlusion and were randomized to receive one of the following treatments: saline (4 ml/kg/h i.v. injection beginning 10 min before the ischemia and continuing for 2 h), insulin (60 U/l, i.v. injection following the same routine, and hypodermic injection of insulin (0.5 U/ml, 1 ml/kg/d) for 3 days after the ischemia surgery) or insulin plus wortmannin (15 μg/kg i.v. injection 15 min before each insulin administration). Treatment with insulin significantly reduced infarct size, decreased plasma creatine kinase and lactate dehydrogenase activities, decreased apoptosis index and caspase-3 activity (all P < 0.01 vs. saline), and improved cardiac function 24 h after ischemia. Importantly, at the end of 4 weeks after the ischemia surgery, MI rats receiving insulin treatment showed smaller left ventricle (LV) cavity and thicker systolic interventricular septum, and increased cardiac ejection fraction and LV fractional shortening (all P < 0.05 vs. saline). Inhibition of insulin signaling with wortmannin not only blocked insulin’s anti-apoptotic effect, but also almost completely abolished effects of insulin on cardiac structure and function. These data indicate that inhibition of apoptosis by early insulin treatment alleviates chronic adverse changes in post-ischemic cardiac structure and function.

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References

  1. Fath-Ordoubadi F, Beatt KJ (1997) Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. Circulation 96:1152–1156

    PubMed  CAS  Google Scholar 

  2. Malmberg K (1997) Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (diabetes mellitus, insulin glucose infusion in acute myocardial infarction) study group. BMJ 314:1512–1515

    PubMed  CAS  Google Scholar 

  3. Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R et al (1998) Metabolic modulation of acute myocardial infarction. The ECLA (estudios cardiologicos latinoamerica) collaborative group. Circulation 98:2227–2234

    PubMed  CAS  Google Scholar 

  4. Gao F, Gao E, Yue TL, Ohlstein EH, Lopez BL, Christopher TA et al (2002) Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 105:1497–1502. doi:10.1161/01.CIR.0000012529.00367.0F

    Article  PubMed  CAS  Google Scholar 

  5. Zhang HF, Fan Q, Qian XX, Lopez BL, Christopher TA, Ma XL et al (2004) Role of insulin in the anti-apoptotic effect of glucose-insulin-potassium in rabbits with acute myocardial ischemia and reperfusion. Apoptosis 9:777–783. doi:10.1023/B:APPT.0000045796.58715.82

    Article  PubMed  CAS  Google Scholar 

  6. Duhamel TA, Dhalla NS (2007) New insights into the causes of heart failure. Drug Discov Today Dis Mech 4:175–184. doi:10.1016/j.ddmec.2007.12.001

    Article  Google Scholar 

  7. French BA, Kramer CM (2007) Mechanisms of post-infarct left ventricular remodeling. Drug Discov Today Dis Mech 4:185–196. doi:10.1016/j.ddmec.2007.12.006

    Article  PubMed  Google Scholar 

  8. Guo X, Saini HK, Wang J, Gupta SK, Goyal RK, Dhalla NS (2005) Prevention of remodeling in congestive heart failure due to myocardial infarction by blockade of the renin-angiotensin system. Expert Rev Cardiovasc Ther 3:717–732. doi:10.1586/14779072.3.4.717

    Article  PubMed  CAS  Google Scholar 

  9. Shiojima I, Yefremashvili M, Luo Z, Kureishi Y, Takahashi A, Tao J et al (2002) Akt signaling mediates postnatal heart growth in response to insulin and nutritional status. J Biol Chem 277:37670–37677. doi:10.1074/jbc.M204572200

    Article  PubMed  CAS  Google Scholar 

  10. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL (1994) Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 94:1621–1628. doi:10.1172/JCI117504

    Article  PubMed  CAS  Google Scholar 

  11. Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM et al (2003) A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 111:1497–1504. doi:10.1172/JCI17664

    PubMed  CAS  Google Scholar 

  12. Baldi A, Abbate A, Bussani R, Patti G, Melfi R, Angelini A et al (2002) Apoptosis and post-infarction left ventricular remodeling. J Mol Cell Cardiol 34:165–174. doi:10.1006/jmcc.2001.1498

    Article  PubMed  CAS  Google Scholar 

  13. Olivetti G, Quaini F, Sala R, Lagrasta C, Corradi D, Bonacina E et al (1996) Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol 28:2005–2016. doi:10.1006/jmcc.1996.0193

    Article  PubMed  CAS  Google Scholar 

  14. Abbate A, Biondi-Zoccai GG, Bussani R, Dobrina A, Camilot D, Feroce F et al (2003) Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure. J Am Coll Cardiol 41:753–760. doi:10.1016/S0735-1097(02)02959-5

    Article  PubMed  Google Scholar 

  15. Matturri L, Milei J, Grana DR, Lavezzi AM (2002) Characterization of myocardial hypertrophy by DNA content, PCNA expression and apoptotic index. Int J Cardiol 82:33–39. doi:10.1016/S0167-5273(01)00578-2

    Article  PubMed  Google Scholar 

  16. Condorelli G, Morisco C, Stassi G, Notte A, Farina F, Sgaramella G et al (1999) Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation 99:3071–3078

    PubMed  CAS  Google Scholar 

  17. Gao F, Tao L, Yan W, Gao E, Liu HR, Lopez BL et al (2004) Early anti-apoptosis treatment reduces myocardial infarct size after a prolonged reperfusion. Apoptosis 9:553–559. doi:10.1023/B:APPT.0000038035.75845.ab

    Article  PubMed  CAS  Google Scholar 

  18. Zhang QJ, Li QX, Zhang HF, Zhang KR, Guo WY, Wang HC et al (2007) Swim training sensitizes myocardial response to insulin: role of Akt-dependent eNOS activation. Cardiovasc Res 75:369–380. doi:10.1016/j.cardiores.2007.04.015

    Article  PubMed  CAS  Google Scholar 

  19. Salloum FN, Abbate A, Das A, Houser JE, Mudrick CA, Qureshi IZ et al (2008) Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. Am J Physiol Heart Circ Physiol 294:H1398–H1406. doi:10.1152/ajpheart.91438.2007

    Article  PubMed  CAS  Google Scholar 

  20. Teichholz LE, Kreulen T, Herman MV, Gorlin R (1976) Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy. Am J Cardiol 37:7–11

    Article  PubMed  CAS  Google Scholar 

  21. Diaz R, Goyal A, Mehta SR, Afzal R, Xavier D, Pais P et al (2007) Glucose-insulin-potassium therapy in patients with ST-segment elevation myocardial infarction. JAMA 298:2399–2405. doi:10.1001/jama.298.20.2399

    Article  PubMed  CAS  Google Scholar 

  22. Su H, Sun X, Ma H, Zhang HF, Yu QJ, Huang C et al (2007) Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury and blunts cardioprotective effect of GIK. Am J Physiol Endocrinol Metab 293:E629–E635. doi:10.1152/ajpendo.00221.2007

    Article  PubMed  CAS  Google Scholar 

  23. Jonassen AK, Sack MN, Mjos OD, Yellon DM (2001) Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 89:1191–1198. doi:10.1161/hh2401.101385

    Article  PubMed  CAS  Google Scholar 

  24. Xydas S, Kherani AR, Chang JS, Klotz S, Hay I, Mutrie CJ et al (2006) Beta(2)-adrenergic stimulation attenuates left ventricular remodeling, decreases apoptosis, and improves calcium homeostasis in a rodent model of ischemic cardiomyopathy. J Pharmacol Exp Ther 317:553–561. doi:10.1124/jpet.105.099432

    Article  PubMed  CAS  Google Scholar 

  25. Xu XB, Pang JJ, Cao JM, Ni C, Xu RK, Peng XZ et al (2005) GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure. Am J Physiol Heart Circ Physiol 289:H1643–H1651

    Article  PubMed  CAS  Google Scholar 

  26. Shibata R, Izumiya Y, Sato K, Papanicolaou K, Kihara S, Colucci WS et al (2007) Adiponectin protects against the development of systolic dysfunction following myocardial infarction. J Mol Cell Cardiol 42:1065–1074. doi:10.1016/j.yjmcc.2007.03.808

    Article  PubMed  CAS  Google Scholar 

  27. Schneider RM, Morris KG, Chu A, Roberts KB, Coleman RE, Cobb FR (1987) Relation between myocardial perfusion and left ventricular function following acute coronary occlusion: disproportionate effects of anterior vs. inferior ischemia. Circ Res 60:60–71

    PubMed  CAS  Google Scholar 

  28. Chaudhuri A, Janicke D, Wilson MF, Tripathy D, Garg R, Bandyopadhyay A et al (2004) Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation 109:849–854. doi:10.1161/01.CIR.0000116762.77804.FC

    Article  PubMed  CAS  Google Scholar 

  29. Dandona P, Chaudhuri A, Ghanim H, Mohanty P (2006) Anti-inflammatory effects of insulin and pro-inflammatory effects of glucose: relevance to the management of acute myocardial infarction and other acute coronary syndromes. Rev Cardiovasc Med 7(Suppl 2):S25–S34

    PubMed  Google Scholar 

  30. Li J, Zhang H, Wu F, Nan Y, Ma H, Guo W et al (2008) Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation. Crit Care Med 36:1551–1558. doi:10.1097/CCM.0b013e3181782335

    Article  PubMed  CAS  Google Scholar 

  31. Aikawa R, Nawano M, Gu Y, Katagiri H, Asano T, Zhu W et al (2000) Insulin prevents cardiomyocytes from oxidative stress-induced apoptosis through activation of PI3 kinase/Akt. Circulation 102:2873–2879

    PubMed  CAS  Google Scholar 

  32. Ma H, Zhang HF, Yu L, Zhang QJ, Li J, Huo JH et al (2006) Vasculoprotective effect of insulin in the ischemic/reperfused canine heart: role of Akt-stimulated NO production. Cardiovasc Res 69:57–65. doi:10.1016/j.cardiores.2005.08.019

    Article  PubMed  CAS  Google Scholar 

  33. Sinha AK, Bhattacharya S, Acharya K, Mazumder S (1999) Stimulation of nitric oxide synthesis and protective role of insulin in acute thrombosis in vivo. Life Sci 65:2687–2696. doi:10.1016/S0024-3205(99)00537-8

    Article  PubMed  CAS  Google Scholar 

  34. Pfeffer MA (1995) Left ventricular remodeling after acute myocardial infarction. Annu Rev Med 46:455–466. doi:10.1146/annurev.med.46.1.455

    Article  PubMed  CAS  Google Scholar 

  35. Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA et al (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141

    Article  PubMed  CAS  Google Scholar 

  36. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ et al (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189

    Article  PubMed  CAS  Google Scholar 

  37. Li Z, Bing OH, Long X, Robinson KG, Lakatta EG (1997) Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol 272:H2313–H2319

    PubMed  CAS  Google Scholar 

  38. Teiger E, Than VD, Richard L, Wisnewsky C, Tea BS, Gaboury L et al (1996) Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 97:2891–2897. doi:10.1172/JCI118747

    Article  PubMed  CAS  Google Scholar 

  39. Saraste A, Pulkki K, Kallajoki M, Heikkila P, Laine P, Mattila S et al (1999) Cardiomyocyte apoptosis and progression of heart failure to transplantation. Eur J Clin Invest 29:380–386. doi:10.1046/j.1365-2362.1999.00481

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the National Science Fund for Outstanding Young Investigators (No.30625033), National Basic Research Program of China (No.2007CB512106), and grants from the National Natural Science Foundation of China (Nos. 30800376, 30800447).

Conflict of interest statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology, Xijing Hospital, Fourth Military Medical University, 710032, Xi’an, China

    Wenjuan Xing, Wenjun Yan, Feng Fu, Lele Ji, Wenchong Liu, Li Wang, Anlin Lv, Haifeng Zhang & Feng Gao

  2. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 710032, Xi’an, China

    Wenjuan Xing, Wenjun Yan, Feng Fu, Lele Ji, Wenchong Liu, Li Wang, Anlin Lv, Haifeng Zhang & Feng Gao

  3. Department of Preventive Medicine, North China Coal Medical College, 063000, Tangshan, China

    Yulan Jin

  4. Department of Ultrasonic Diagnosis, Xijing Hospital, Fourth Military Medical University, 710032, Xi’an, China

    Yunyan Duan & Jun Zhang

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  1. Wenjuan Xing
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Correspondence to Haifeng Zhang or Feng Gao.

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Wenjuan Xing and Wenjun Yan contributed equally to this study.

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Xing, W., Yan, W., Fu, F. et al. Insulin inhibits myocardial ischemia-induced apoptosis and alleviates chronic adverse changes in post-ischemic cardiac structure and function. Apoptosis 14, 1050–1060 (2009). https://doi.org/10.1007/s10495-009-0378-y

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