Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress.

It is well known that insulin possesses a cardioprotective effect and that insulin resistance is closely related to cardiovascular diseases. Peroxynitrite (ONOO(-)) formation may trigger oxidative/nitrative stress and represent a major cytotoxic effect in heart diseases. This study was designed to investigate whether insulin attenuates ONOO(-) generation and oxidative/nitrative stress in acute myocardial ischemia/reperfusion (MI/R). Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. Rats randomly received vehicle, insulin, or insulin plus wortmannin. Arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Insulin significantly improved cardiac functions and reduced myocardial infarction, apoptotic cell death, and blood creatine kinase/lactate dehydrogenase levels following MI/R. Myocardial ONOO(-) formation was significantly attenuated after insulin treatment. Moreover, insulin resulted in a significant increase in Akt and endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and antioxidant capacity in ischemic/reperfused myocardial tissue. On the other hand, insulin markedly reduced MI/R-induced inducible NOS (iNOS) and gp91(phox) expression in cardiac tissue. Inhibition of insulin signaling with wortmannin not only blocked the cardioprotection of insulin but also markedly attenuated insulin-induced antioxidative/antinitrative effect. Furthermore, the suppression on ONOO(-) formation by either insulin or an ONOO(-) scavenger uric acid reduced myocardial infarct size in rats subjected to MI/R. We concluded that insulin exerts a cardioprotective effect against MI/R injury by blocking ONOO(-) formation. Increased physiological NO production (via eNOS phosphorylation) and superoxide anion reduction contribute to the antioxidative/antinitrative effect of insulin, which can be reversed by inhibiting phosphatidylinositol 3'-kinase. These results provide important novel information on the mechanisms of cardiovascular actions of insulin.

[1]  F. Gao,et al.  Insulin inhibits myocardial ischemia-induced apoptosis and alleviates chronic adverse changes in post-ischemic cardiac structure and function , 2009, Apoptosis.

[2]  Yajing Wang,et al.  INO-4885 [5,10,15,20-Tetra[N-(benzyl-4′-carboxylate)-2-pyridinium]-21H,23H-porphine Iron(III) Chloride], a Peroxynitrite Decomposition Catalyst, Protects the Heart against Reperfusion Injury in Mice , 2009, Journal of Pharmacology and Experimental Therapeutics.

[3]  S. Belmadani,et al.  Role of TNF-alpha-induced reactive oxygen species in endothelial dysfunction during reperfusion injury. , 2008, American journal of physiology. Heart and circulatory physiology.

[4]  W. Bremner,et al.  Advances in male contraception. , 2008, Endocrine reviews.

[5]  F. Gao,et al.  Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity. , 2007, American journal of physiology. Endocrinology and metabolism.

[6]  P. Kuppusamy,et al.  Inhibition of peroxynitrite precursors, NO and O2, at the onset of reperfusion improves myocardial recovery. , 2007, Resuscitation.

[7]  F. Gao,et al.  Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury and blunts cardioprotective effect of GIK. , 2007, American journal of physiology. Endocrinology and metabolism.

[8]  R. Muniyappa,et al.  Cardiovascular actions of insulin. , 2007, Endocrine reviews.

[9]  F. Gao,et al.  Long-term aerobic exercise protects the heart against ischemia/reperfusion injury via PI3 kinase-dependent and Akt-mediated mechanism , 2007, Apoptosis.

[10]  B. Lopez,et al.  Role of iNOS-derived reactive nitrogen species and resultant nitrative stress in leukocytes-induced cardiomyocyte apoptosis after myocardial ischemia/reperfusion , 2007, Apoptosis.

[11]  B. Pesse,et al.  Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo. , 2006, Free radical biology & medicine.

[12]  J. Zweier,et al.  The role of oxidants and free radicals in reperfusion injury. , 2006, Cardiovascular research.

[13]  M. Quon,et al.  Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms , 2006, Circulation.

[14]  Ilse Vanhorebeek,et al.  Intensive insulin therapy protects the endothelium of critically ill patients. , 2005, The Journal of clinical investigation.

[15]  A. Zaidi,et al.  Myocardial ischaemia and reperfusion injury: reactive oxygen species and the role of neutrophil. , 2005, Journal of the College of Physicians and Surgeons--Pakistan : JCPSP.

[16]  W. Paulus,et al.  Peroxynitrite-induced alpha-actinin nitration and contractile alterations in isolated human myocardial cells. , 2005, Cardiovascular research.

[17]  C. Szabó,et al.  Nitrosative stress and pharmacological modulation of heart failure. , 2005, Trends in pharmacological sciences.

[18]  C. Vrints,et al.  Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process. , 2005, International journal of cardiology.

[19]  B. Lopez,et al.  Role of insulin in the anti-apoptotic effect of glucose-insulin-potassium in rabbits with acute myocardial ischemia and reperfusion , 2004, Apoptosis.

[20]  T. Christopher,et al.  Critical Timing of L‐arginine Treatment in Post‐Ischemic Myocardial Apoptosis‐Role of NOS Isoforms: 171 , 2004, Cardiovascular research.

[21]  A. Hsu,et al.  Opioid-Induced Cardioprotection Occurs via Glycogen Synthase Kinase β Inhibition During Reperfusion in Intact Rat Hearts , 2004, Circulation research.

[22]  Jun Ren,et al.  Cardiac-specific overexpression of catalase rescues ventricular myocytes from ethanol-induced cardiac contractile defect. , 2003, Journal of molecular and cellular cardiology.

[23]  É. Szabó,et al.  Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. , 2003, Toxicology letters.

[24]  P. Ferdinandy,et al.  Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia‐reperfusion injury and preconditioning , 2003, British journal of pharmacology.

[25]  U. Förstermann,et al.  Physiological mechanisms regulating the expression of endothelial-type NO synthase. , 2002, Nitric oxide : biology and chemistry.

[26]  F. Gao,et al.  Ischemia-Reperfusion : The Roles of PI 3-Kinase , Akt , and Endothelial Nitric Oxide Nitric Oxide Mediates the Antiapoptotic Effect of Insulin in Myocardial , 2002 .

[27]  F. Gao,et al.  p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation. , 2002, Cardiovascular research.

[28]  A. Aljada,et al.  Insulin Inhibits Intranuclear Nuclear Factor κB and Stimulates IκB in Mononuclear Cells in Obese Subjects: Evidence for an Anti-inflammatory Effect? , 2001 .

[29]  R. Diaz.  Metabolic modulation of acute myocardial infarction. , 2001, Critical care clinics.

[30]  A. Zeiher,et al.  Nitric Oxide Down-regulates MKP-3 mRNA Levels , 2000, The Journal of Biological Chemistry.

[31]  N. Dhalla,et al.  Status of myocardial antioxidants in ischemia-reperfusion injury. , 2000, Cardiovascular research.

[32]  T. Billiar,et al.  Nitric oxide as a bifunctional regulator of apoptosis. , 1999, Circulation research.

[33]  L. Piegas,et al.  Metabolic Modulation of Acute Myocardial Infarction The ECLA Glucose-Insulin-Potassium Pilot Trial , 1998 .

[34]  T. Gardner,et al.  Recombinant adenovirus-mediated cardiac gene transfer of superoxide dismutase and catalase attenuates postischemic contractile dysfunction. , 1998, Circulation.

[35]  B. Lopez,et al.  Peroxynitrite aggravates myocardial reperfusion injury in the isolated perfused rat heart. , 1997, Cardiovascular research.

[36]  K. Beatt,et al.  Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. , 1997, Circulation.

[37]  P. Kaminski,et al.  Lactate and PO2 modulate superoxide anion production in bovine cardiac myocytes: potential role of NADH oxidase. , 1997, Circulation.

[38]  K. Malmberg.  Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus , 1997, BMJ.

[39]  Peitan Liu,et al.  Formation of nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury in rats. , 1997, The American journal of physiology.

[40]  B. Lopez,et al.  Peroxynitrite, the product of nitric oxide and superoxide, causes myocardial injury in the isolated perfused rat heart. , 1997, Coronary artery disease.

[41]  M. Nehls,et al.  Suppression of Apoptosis by Nitric Oxide via Inhibition of Interleukin-1β–converting Enzyme (ICE)-like and Cysteine Protease Protein (CPP)-32–like Proteases , 1997, The Journal of experimental medicine.

[42]  R. Schulz,et al.  Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. , 1997, Cardiovascular research.

[43]  J. Zweier,et al.  Measurement of Nitric Oxide and Peroxynitrite Generation in the Postischemic Heart , 1996, The Journal of Biological Chemistry.

[44]  B. Freeman,et al.  Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[45]  PhD Cuihua Zhang MD.  The role of inflammatory cytokines in endothelial dysfunction , 2008, Basic Research in Cardiology.

[46]  F. Gao,et al.  Vasculoprotective effect of insulin in the ischemic/reperfused canine heart: role of Akt-stimulated NO production. , 2006, Cardiovascular research.

[47]  R. Schulz,et al.  Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2. , 2002, Cardiovascular research.

[48]  A. Aljada,et al.  Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? , 2001, The Journal of clinical endocrinology and metabolism.

[49]  R. Diaz,et al.  Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiológicos Latinoamérica) Collaborative Group. , 1998, Circulation.

[50]  Y. Hirota,et al.  Peroxynitrite-induced cardiac myocyte injury. , 1996, Free radical biology & medicine.