Circulation Research. 2001;89:1191-1198
Published online before print November 8, 2001, doi: 10.1161/hh2401.101385
Published online before print November 8, 2001, doi: 10.1161/hh2401.101385
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© 2001 American Heart Association, Inc.
Integrative Physiology |
Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling
From the Department of Medical Physiology (A.K.J., O.D.M.), Institute of Medical Biology, University of Tromsø, Norway; the Hatter Institute for Cardiology Research (A.K.J., M.N.S.), Cape Heart Centre, University of Cape Town, South Africa; and the Hatter Institute (D.M.Y.), University College London Hospitals and Medical School, London, UK.
Correspondence to Derek M. Yellon, PhD, DSc, the Hatter Institute and Centre for Cardiology, University College London Hospitals and Medical School, Grafton Way, London WC1E 6DB, UK. E-mail hatter-institute{at}ucl.ac.uk
The "metabolic cocktail" comprising glucose-insulin-potassium administrated at reperfusion reduces infarct size in the in vivo rat heart. We propose that insulin is the major component mediating this protection and acts via Akt prosurvival signaling. This hypothesis was studied in isolated perfused rat hearts (measuring infarct size to area of risk [%]) subjected to 35 minutes regional myocardial ischemia and 2 hours reperfusion. Insulin administered at the onset of reperfusion attenuated infarct size by 
45% versus control hearts (P<0.001). Insulin-mediated cardioprotection was found to be independent of the presence of glucose at reperfusion. Moreover, the cell survival benefit of insulin is temporally dependent, in that insulin administration from the onset of reperfusion and maintained for either 15 minutes or for the duration of reperfusion reduced infarct size. In contrast, protection was abrogated if insulin administration was delayed until 15 minutes into reperfusion. Pharmacological inhibition of both upstream and downstream signals in the Akt prosurvival pathway abolished the cardioprotective effects of insulin. Here coadministration of insulin with the tyrosine kinase inhibitor lavendustin A, the phosphatidylinositol3-kinase (PI3-kinase) inhibitor wortmannin, and mTOR/p70s6 kinase inhibitor rapamycin abolished cardioprotection. Steady-state levels of activated/phosphorylated Akt correlated with insulin administration. Finally, downstream prosurvival targets of Akt including p70s6 kinase and BAD were modulated by insulin. In conclusion, insulin administration at reperfusion reduces myocardial infarction, is dependent on early administration during reperfusion, and is mediated via Akt and p70s6 kinase dependent signaling pathway. Moreover, BAD is maintained in its inert phosphorylated state in response to insulin therapy.
Key Words: cardioprotection • insulin • Akt • p70s6 kinase • BAD
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J. B. C. Carvalheira, V. C. Calegari, H. G. Zecchin, W. Nadruz Jr., R. B. Guimaraes, E. B. Ribeiro, K. G. Franchini, L. A. Velloso, and M. J. A. Saad The Cross-Talk between Angiotensin and Insulin Differentially Affects Phosphatidylinositol 3-Kinase- and Mitogen-Activated Protein Kinase-Mediated Signaling in Rat Heart: Implications for Insulin Resistance Endocrinology, December 1, 2003; 144(12): 5604 - 5614. [Abstract] [Full Text] [PDF]
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T.-M. Lee and T.-F. Chou Troglitazone administration limits infarct size by reduced phosphorylation of canine myocardial connexin43 proteins Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1650 - H1659. [Abstract] [Full Text] [PDF]
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C. S. Apstein The benefits of glucose-insulin-potassium for acute myocardial infarction (and some concerns) J. Am. Coll. Cardiol., September 3, 2003; 42(5): 792 - 795. [Full Text] [PDF]
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P. Dandona, A. Aljada, and A. Bandyopadhyay Hyperglycemia After Myocardial Infarction: Response to Dhatariya Diabetes Care, July 1, 2003; 26(7): 2222 - 2223. [Full Text] [PDF]
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M. E. Jessen Glucose control during cardiac surgery: How sweet it is J. Thorac. Cardiovasc. Surg., May 1, 2003; 125(5): 985 - 987. [Full Text] [PDF]
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Z. T. Bloomgarden Inflammation and Insulin Resistance Diabetes Care, May 1, 2003; 26(5): 1619 - 1623. [Full Text] [PDF]
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M. N. Sack and D. M. Yellon Insulin therapy as an adjunct toreperfusion after acute coronary ischemia: A proposed direct myocardial cell survival effect independent of metabolic modulation J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1404 - 1407. [Abstract] [Full Text] [PDF]
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L. Calvillo, R. Latini, J. Kajstura, A. Leri, P. Anversa, P. Ghezzi, M. Salio, A. Cerami, and M. Brines Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling PNAS, April 15, 2003; 100(8): 4802 - 4806. [Abstract] [Full Text] [PDF]
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R. M. Bell and D. M. Yellon Atorvastatin, administered at the onset of reperfusion, and independent oflipid lowering, protects the myocardiumby up-regulating a pro-survival pathway J. Am. Coll. Cardiol., February 5, 2003; 41(3): 508 - 515. [Abstract] [Full Text] [PDF]
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T. Doenst, W. Bothe, and F. Beyersdorf Therapy with insulin in cardiac surgery: controversies and possible solutions Ann. Thorac. Surg., February 1, 2003; 75(2): S721 - 728. [Abstract] [Full Text] [PDF]
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J. Yang, A. K. Gillingham, A. Hodel, F. Koumanov, B. Woodward, and G. D. Holman Insulin-stimulated cytosol alkalinization facilitates optimal activation of glucose transport in cardiomyocytes Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1299 - E1307. [Abstract] [Full Text] [PDF]
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C. Depre, M. Hase, V. Gaussin, A. Zajac, L. Wang, L. Hittinger, B. Ghaleh, X. Yu, R. K. Kudej, T. Wagner, et al. H11 Kinase Is a Novel Mediator of Myocardial Hypertrophy In Vivo Circ. Res., November 29, 2002; 91(11): 1007 - 1014. [Abstract] [Full Text] [PDF]
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S. A. Cook, T. Matsui, L. Li, and A. Rosenzweig Transcriptional Effects of Chronic Akt Activation in the Heart J. Biol. Chem., June 14, 2002; 277(25): 22528 - 22533. [Abstract] [Full Text] [PDF]
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