This study examined the hypothesis that acute hyperglycemia (HG) blocks ischemic preconditioning (IPC) by inhibiting Akt phosphorylation. Brief HG of approximately 400？mg/dL was induced in C57BL/6 mice via intraperitoneal injection of 20% dextrose (2？g/kg). All mice underwent 40？min LAD occlusion and 60？min reperfusion. The IPC protocol was 2 cycles of 5？min ischemia and 5？min reperfusion prior to index ischemia. Results. In control mice, infarct size (IF) was 51.7 ± 2.0 (% risk region). Preconditioning reduced IF by 50% to 25.8 ± 3.2 ( versus control). In HG mice, IF was significantly exacerbated to 58.1 ± 2.3. However, the effect of IPC completely disappeared in HG mice. Normalization of blood glucose with insulin 5 min before IPC recovered the cardioprotective effect. Administration of CCPA before index ischemia mimicked IPC effect. The cardioprotective effect of CCPA, not its chronotropic effect, completely disappeared in HG mice. Phosphorylation of cardiac tissue Akt before index ischemia was enhanced by IPC or CCPA but was significantly inhibited by HG in both groups. Normalization of glucose with insulin reversed the inhibition of Akt phosphorylation by HG. Conclusion. HG abolishes the cardioprotective effect of preconditioning by inhibiting Akt phosphorylation. Normalization of blood glucose with insulin suffices to recover the cardioprotective effect of preconditioning. 1. Introduction Hyperglycemia is commonly present in the perioperative period in patients undergoing cardiac surgery [1–3]. Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality and morbidity in both diabetic and nondiabetic patients [3]. An increasing body of clinical evidence has shown that acute hyperglycemia (or stress hyperglycemia) is independently associated with larger myocardial infarct (MI) size and impaired left ventricular function in both diabetic and nondiabetic patients [4–6]. Animal studies have also shown that the size of MI increases in response to elevations in blood glucose levels [7, 8]. Ischemic preconditioning is a powerful endogenous protective mechanism against myocardial ischemia/reperfusion injury, which is induced by brief episodes of ischemia and reperfusion before the prolonged index myocardial ischemia and reperfusion [9]. However, diabetes mellitus and acute hyperglycemia have been shown to counteract the cardioprotective effects of both ischemic and pharmacological preconditioning in animals and humans [7, 10–12]. The mechanisms underlying the hyperglycemic blockade of preconditioning remain to be defined.
References
[1]
H. L. Lazar, “Hyperglycemia during cardiac surgery,” Journal of Thoracic and Cardiovascular Surgery, vol. 131, no. 1, pp. 11–13, 2006.
[2]
D. W. Quinn, D. Pagano, R. S. Bonser et al., “Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: a randomized controlled trial,” Journal of Thoracic and Cardiovascular Surgery, vol. 131, no. 1, pp. 34.e2–42.e2, 2006.
[3]
T. Doenst, D. Wijeysundera, K. Karkouti et al., “Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery,” Journal of Thoracic and Cardiovascular Surgery, vol. 130, no. 4, pp. 1144.e1–1144.e8, 2005.
[4]
M. Ishihara, I. Inoue, T. Kawagoe et al., “Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction,” American Heart Journal, vol. 146, no. 4, pp. 674–678, 2003.
[5]
R. Marfella, M. Siniscalchi, K. Esposito et al., “Effects of stress hyperglycemia on acute myocardial infarction: role of inflammatory immune process in functional cardiac outcome,” Diabetes Care, vol. 26, no. 11, pp. 3129–3135, 2003.
[6]
N. N. Wahab, E. A. Cowden, N. J. Pearce, M. J. Gardner, H. Merry, and J. L. Cox, “Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era?” Journal of the American College of Cardiology, vol. 40, no. 10, pp. 1748–1754, 2002.
[7]
J. R. Kersten, W. G. Toller, E. R. Gross, P. S. Pagel, and D. C. Warltier, “Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 278, no. 4, pp. H1218–H1224, 2000.
[8]
Z. Yang, V. E. Laubach, B. A. French, and I. L. Kron, “Acute hyperglycemia enhances oxidative stress and exacerbates myocardial infarction by activating nicotinamide adenine dinucleotide phosphate oxidase during reperfusion,” Journal of Thoracic and Cardiovascular Surgery, vol. 137, no. 3, pp. 723–729, 2009.
[9]
L. H. Opie, “Preconditioning and metabolic anti-ischaemic agents,” European Heart Journal, vol. 24, no. 20, pp. 1854–1856, 2003.
[10]
J. R. Kersten, “Acute hyperglycemia abolishes ischemic preconditioning in vivo,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 275, no. 2, pp. H721–H725, 1998.
[11]
J. R. Kersten, M. W. Montgomery, T. Ghassemi et al., “Diabetes and hyperglycemia impair activation of mitochondrial KATP channels,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 280, no. 4, pp. H1744–H1750, 2001.
[12]
D. Ebel, O. Toma, S. Appler et al., “Ischemic preconditioning phosphorylates mitogen-activated kinases and heat shock protein 27 in the diabetic rat heart,” Hormone and Metabolic Research, vol. 41, no. 1, pp. 10–15, 2009.
[13]
C. J. Zuurbier, “Insulin as ischaemic preconditioning-mimetic,” Acta Physiologica, vol. 195, no. 2, p. 203, 2009.
[14]
C. J. Zuurbier, O. Eerbeek, and A. J. Meijer, “Ischemic preconditioning, insulin, and morphine all cause hexokinase redistribution,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 289, no. 1, pp. H496–H499, 2005.
[15]
D. Ebel, J. Müllenheim, J. Fr？？dorf et al., “Effect of acute hyperglycaemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischaemic late preconditioning in the rabbit heart in vivo,” Pflugers Archiv European Journal of Physiology, vol. 446, no. 2, pp. 175–182, 2003.
[16]
S. Forlani, F. Tomai, R. De Paulis et al., “Preoperative shift from glibenclamide to insulin is cardioprotective in diabetic patients undergoing coronary artery bypass surgery,” Journal of Cardiovascular Surgery, vol. 45, no. 2, pp. 117–122, 2004.
[17]
H. F. Del Valle, E. C. Lascano, and J. A. Negroni, “Ischemic preconditioning protection against stunning in conscious diabetic sheep: role of glucose, insulin, sarcolemmal and mitochondrial KATP channels,” Cardiovascular Research, vol. 55, no. 3, pp. 642–659, 2002.
[18]
J. D. Mccully, Y. Toyoda, M. Uematsu, R. D. Stewart, and S. Levitsky, “Adenosine-enhanced ischemic preconditioning: adenosine receptor involvement during ischemia and reperfusion,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 280, no. 2, pp. H591–H602, 2001.
[19]
Z.-Q. Zhao, K. Nakanishi, D. S. McGee, P. Tan, and J. Vinten-Johansen, “A1 Receptor mediated myocardial infarct size reduction by endogenous adenosine is exerted primarily during ischaemia,” Cardiovascular Research, vol. 28, no. 2, pp. 270–279, 1994.
[20]
Z. Yang, R. L. J. Cerniway, A. M. Byford, S. S. Berr, B. A. French, and G. Paul Matherne, “Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 282, no. 3, pp. H949–H955, 2002.
[21]
H. Takano, R. Bolli, R. G. Black Jr. et al., “A1 or A3 adenosine receptors induce late preconditioning against infarction in conscious rabbits by different mechanisms,” Circulation Research, vol. 88, no. 5, pp. 520–528, 2001.
[22]
M. E. Reichelt, A. Shanu, L. Willems et al., “Endogenous adenosine selectively modulates oxidant stress via the A1 receptor in ischemic hearts,” Antioxidants and Redox Signaling, vol. 11, no. 11, pp. 2641–2650, 2009.
[23]
A. R. Lankford, J.-N. Yang, R. Rose'Meyer et al., “Effect of modulating cardiac A1 adenosine receptor expression on protection with ischemic preconditioning,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 290, no. 4, pp. H1469–H1473, 2006.
[24]
E. Giannella, H.-C. Mochmann, and R. Levi, “Ischemic preconditioning prevents the impairment of hypoxic coronary vasodilatation caused by ischemia/reperfusion: role of adenosine A1/A3 and bradykinin B2 receptor activation,” Circulation Research, vol. 81, no. 3, pp. 415–422, 1997.
[25]
Z. Yang, Y.-J. Day, M.-C. Toufektsian et al., “Infarct-sparing effect of A2A-adenosine receptor activation is due primarily to its action on lymphocytes,” Circulation, vol. 111, no. 17, pp. 2190–2197, 2005.
[26]
Z. Yang, Y.-J. Day, M.-C. Toufektsian et al., “Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes,” Circulation, vol. 114, no. 19, pp. 2056–2064, 2006.
[27]
S. E. Capes, D. Hunt, K. Malmberg, and H. C. Gerstein, “Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview,” The Lancet, vol. 355, no. 9206, pp. 773–778, 2000.
[28]
M. Ishihara, S. Kojima, T. Sakamoto et al., “Acute hyperglycemia is associated with adverse outcome after acute myocardial infarction in the coronary intervention era,” American Heart Journal, vol. 150, no. 4, pp. 814–820, 2005.
[29]
K. A. Webster, “Stress hyperglycemia and enhanced sensitivity to myocardial infarction,” Current Hypertension Reports, vol. 10, no. 1, pp. 78–84, 2008.
[30]
Y. Hu, G. Block, E. P. Norkus, J. D. Morrow, M. Dietrich, and M. Hudes, “Relations of glycemic index and glycemic load with plasma oxidative stress markers,” American Journal of Clinical Nutrition, vol. 84, no. 1, pp. 70–76, 2006.
[31]
H. Kawano, T. Motoyama, O. Hirashima et al., “Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery,” Journal of the American College of Cardiology, vol. 34, no. 1, pp. 146–154, 1999.
[32]
P. Mohanty, W. Hamouda, R. Garg, A. Aljada, H. Ghanim, and P. Dandona, “Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 8, pp. 2970–2973, 2000.
[33]
M. G. Rosca, T. G. Mustata, M. T. Kinter et al., “Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation,” American Journal of Physiology—Renal Physiology, vol. 289, no. 2, pp. F420–F430, 2005.
[34]
D. Sudic, M. Razmara, M. Forslund, Q. Ji, P. Hjemdahl, and N. Li, “High glucose levels enhance platelet activation: involvement of multiple mechanisms,” British Journal of Haematology, vol. 133, no. 3, pp. 315–322, 2006.
[35]
A. Aljada, J. Friedman, H. Ghanim et al., “Glucose ingestion induces an increase in intranuclear nuclear factor κB, a fall in cellular inhibitor κB, and an increase in tumor necrosis factor α messenger RNA by mononuclear cells in healthy human subjects,” Metabolism, vol. 55, no. 9, pp. 1177–1185, 2006.
[36]
S. Dhindsa, D. Tripathy, P. Mohanty et al., “Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-κB in mononuclear cells,” Metabolism, vol. 53, no. 3, pp. 330–334, 2004.
[37]
Y. Iwasaki, M. Kambayashi, M. Asai, M. Yoshida, T. Nigawara, and K. Hashimoto, “High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro,” Journal of Diabetes and its Complications, vol. 21, no. 1, pp. 56–62, 2007.
[38]
S. W. Zarich and R. W. Nesto, “Implications and treatment of acute hyperglycemia in the setting of acute myocardial infarction,” Circulation, vol. 115, no. 18, pp. e436–e439, 2007.
[39]
N. C. Weber, C. Goletz, R. Huhn et al., “Blockade of anaesthetic-induced preconditioning in the hyperglycaemic myocardium. The regulation of different mitogen-activated protein kinases,” European Journal of Pharmacology, vol. 592, no. 1–3, pp. 48–54, 2008.
[40]
M. Ishihara, I. Inoue, T. Kawagoe et al., “Effect of acute hyperglycemia on the ischemic preconditioning effect of prodromal angina pectoris in patients with a first anterior wall acute myocardial infarction,” American Journal of Cardiology, vol. 92, no. 3, pp. 288–291, 2003.
[41]
F. Kehl, J. G. Krolikowski, D. Weihrauch, P. S. Pagel, D. C. Warltier, and J. R. Kersten, “N-acetylcysteine restores isoflurane-induced preconditioning against myocardial infarction during hyperglycemia,” Anesthesiology, vol. 98, no. 6, pp. 1384–1390, 2003.
[42]
F. B. Stentz and A. E. Kitabchi, “Hyperglycemia-induced activation of human T-lymphocytes with de novo emergence of insulin receptors and generation of reactive oxygen species,” Biochemical and Biophysical Research Communications, vol. 335, no. 2, pp. 491–495, 2005.
[43]
S. Matsumoto, S. Cho, S. Tosaka et al., “Pharmacological preconditioning in type 2 diabetic rat hearts: the roles of mitochondrial atp-sensitive potassium channels and the phosphatidylinositol 3-kinase-akt pathway,” Cardiovascular Drugs and Therapy, vol. 23, no. 4, pp. 263–270, 2009.
[44]
A. Tsang, D. J. Hausenloy, M. M. Mocanu, R. D. Carr, and D. M. Yellon, “Preconditioning the diabetic heart: the importance of Akt phosphorylation,” Diabetes, vol. 54, no. 8, pp. 2360–2364, 2005.
[45]
H. F. del Valle, E. C. Lascano, J. A. Negroni, and A. J. Crottogini, “Absence of ischemic preconditioning protection in diabetic sheep hearts: role of sarcolemmal KATP channel dysfunction,” Molecular and Cellular Biochemistry, vol. 249, no. 1-2, pp. 21–30, 2003.
[46]
A. K. Jonassen, M. N. Sack, O. D. Mj？s, and D. M. Yellon, “Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling,” Circulation Research, vol. 89, no. 12, pp. 1191–1198, 2001.
[47]
H. P. Selker, J. R. Beshansky, P. R. Sheehan, et al., “Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial,” Journal of the American Medical Association, vol. 307, pp. 1925–1933, 2012.
[48]
Z. Yang, J. Linden, S. S. Berr, I. L. Kron, G. A. Beller, and B. A. French, “Timing of adenosine 2A receptor stimulation relative to reperfusion has differential effects on infarct size and cardiac function as assessed in mice by MRI,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 295, no. 6, pp. H2328–H2335, 2008.
[49]
X. Yang, M. V. Cohen, and J. M. Downey, “Mechanism of cardioprotection by early ischemic preconditioning,” Cardiovascular Drugs and Therapy, vol. 24, no. 3, pp. 225–234, 2010.
[50]
G. Zeng, F. H. Nystrom, L. V. Ravichandran et al., “Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells,” Circulation, vol. 101, no. 13, pp. 1539–1545, 2000.
[51]
X.-Q. Zeng, C.-M. Zhang, M.-L. Tong et al., “Knockdown of NYGGF4 increases glucose transport in C2C12 mice skeletal myocytes by activation IRS-1/PI3K/AKT insulin pathway,” Journal of Bioenergetics and Biomembranes, vol. 44, no. 3, pp. 351–355, 2012.
[52]
T. Chen, G. Ding, Z. Jin, et al., “Insulin ameliorates miR-1-induced injury in H9c2 cells under oxidative stress via Akt activation,” Molecular and Cellular Biochemistry, vol. 369, pp. 167–174, 2012.
