HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yue, T.-L. Articles by Jucker, B. M. Search for Related Content PubMed PubMed Citation Articles by Yue, T.-L. Articles by Jucker, B. M. Social Bookmarking                What's this?

Rosiglitazone Treatment in Zucker Diabetic Fatty Rats Is Associated With Ameliorated Cardiac Insulin Resistance and Protection From Ischemia/Reperfusion-Induced Myocardial Injury

From the Department of Investigative and Cardiac Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

The mechanism responsible for the enhanced myocardial susceptibility to ischemic insult in patients with type 2 diabetes is not clear. The present study examines the effect of rosiglitazone treatment on cardiac insulin sensitization and its association with cardioprotection from ischemia/reperfusion injury in an animal model of diabetes. Male Zucker diabetic fatty (ZDF) rats were treated with rosiglitazone (3 mg · kg^–1 · day^–1 orally) or vehicle for 8 days before undergoing 30 min of coronary artery ligation, followed by reperfusion for 4 h (apoptosis) or 24 h (infarction). Rosiglitazone reduced the blood levels of glucose, triglycerides, and free fatty acids; enhanced cardiac glucose oxidation; and increased Akt phosphorylation (Akt-pS473) 2.1-fold and Akt kinase activity 1.8-fold in the ischemic myocardium. The phosphorylation of two downstream targets of Akt, glycogen synthase kinase-3ß and FKHR (forkhead transcription factor), was also enhanced by 2- and 2.9-fold, respectively. In rosiglitazone-treated rats, the number of apoptotic cardiomyocytes and the myocardial infarct size were decreased by 58 and 46%, respectively, and the myocardial contractile dysfunction was improved. Blockade of the insulin-Akt signaling pathway by wortmannin in the 8-day rosiglitazone-treated ZDF rats resulted in a markedly diminished cardioprotective effect of rosiglitazone. In addition, 8-day rosiglitazone treatment in Zucker lean rats or 2-day rosiglitazone treatment in ZDF rats, both of which showed no change in whole-body insulin sensitivity, resulted in a significant reduction in cardiac infarct size, but to a lesser degree when compared with that observed in 8-day rosiglitazone–treated ZDF rats. These results suggest that chronic treatment with rosiglitazone protects the heart against ischemia/reperfusion injury in ZDF rats, and that the enhanced cardiac protection observed after rosiglitazone treatment might be attributable in part to an improvement in cardiac insulin sensitivity.

Abbreviations: DAPI, 4',6-diamidino-2-phenylindole; GSK, glycogen synthase kinase; LV, left ventricular; NMR, nuclear magnetic resonance; PI, phosphatidylinositol; PPAR, peroxisome proliferator–activated receptor; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. G. Bucciarelli, R. Ananthakrishnan, Y. C. Hwang, M. Kaneko, F. Song, D. R. Sell, C. Strauch, V. M. Monnier, S. F. Yan, A. M. Schmidt, et al. RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium Diabetes, July 1, 2008; 57(7): 1941 - 1951. [Abstract] [Full Text] [PDF]

				G. D. Lopaschuk, C. D.L. Folmes, and W. C. Stanley Cardiac Energy Metabolism in Obesity Circ. Res., August 17, 2007; 101(4): 335 - 347. [Abstract] [Full Text] [PDF]

				S. Boudina and E. D. Abel Diabetic Cardiomyopathy Revisited Circulation, June 26, 2007; 115(25): 3213 - 3223. [Abstract] [Full Text] [PDF]

				J. D. Brown and J. Plutzky Peroxisome Proliferator Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets Circulation, January 30, 2007; 115(4): 518 - 533. [Abstract] [Full Text] [PDF]

				D. An and B. Rodrigues Role of changes in cardiac metabolism in development of diabetic cardiomyopathy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1489 - H1506. [Abstract] [Full Text] [PDF]

				Y. Ye, Y. Lin, S. Atar, M.-H. Huang, J. R. Perez-Polo, B. F. Uretsky, and Y. Birnbaum Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1158 - H1169. [Abstract] [Full Text] [PDF]

				Y. Taniguchi, T. Ooie, N. Takahashi, T. Shinohara, M. Nakagawa, H. Yonemochi, M. Hara, H. Yoshimatsu, and T. Saikawa Pioglitazone but not glibenclamide improves cardiac expression of heat shock protein 72 and tolerance against ischemia/reperfusion injury in the heredity insulin-resistant rat. Diabetes, August 1, 2006; 55(8): 2371 - 2378. [Abstract] [Full Text] [PDF]

				B. Clodfelder-Miller, P. De Sarno, A. A. Zmijewska, L. Song, and R. S. Jope Physiological and Pathological Changes in Glucose Regulate Brain Akt and Glycogen Synthase Kinase-3 J. Biol. Chem., December 2, 2005; 280(48): 39723 - 39731. [Abstract] [Full Text] [PDF]

				D. G. Johns, Z. Ao, M. Eybye, A. Olzinski, M. Costell, S. Gruver, S. A. Smith, S. A. Douglas, and C. H. Macphee Rosiglitazone Protects against Ischemia/Reperfusion-Induced Leukocyte Adhesion in the Zucker Diabetic Fatty Rat J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1020 - 1027. [Abstract] [Full Text] [PDF]