Circulation. 2001;104:2588-2594
doi: 10.1161/hc4601.099403
doi: 10.1161/hc4601.099403
(Circulation. 2001;104:2588.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
In Vivo Myocardial Protection From Ischemia/Reperfusion Injury by the Peroxisome Proliferator–Activated Receptor-
Agonist Rosiglitazone
From the Departments of Cardiovascular Pharmacology (T.Y., J.C., W.B., A.B., W.J., P.G.L., J.G., R.E.B., E.H.O.) and Safety Assessment (P.K.N., R.B., D.M.Z., T.K.H.), GlaxoSmithKline Pharmaceuticals, King of Prussia, Pa.
Correspondence to Tian-li Yue, PhD, Department of Cardiovascular Pharmacology, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Rd, PO Box 1539, UW2510, King of Prussia, PA 19406. E-mail tian-li_yue{at}sbphrd.com
Background Diabetes is associated with increased risk of mortality as a consequence of acute myocardial infarction. This study determined whether rosiglitazone (ROSI) could reduce myocardial infarction after ischemia/reperfusion injury.
Methods and Results Male Lewis rats were anesthetized, and the left anterior descending coronary artery was ligated for 30 minutes. After reperfusion for 24 hours, the ischemic and infarct sizes were determined. ROSI at 1 and 3 mg/kg IV reduced infarct size by 30% and 37%, respectively (P<0.01 versus vehicle). Pretreatment with ROSI (3 mg · kg-1 · d-1 PO) for 7 days also reduced infarct size by 24% (P<0.01). ROSI also improved ischemia/reperfusion-induced myocardial contractile dysfunction. Left ventricular systolic pressure and positive and negative maximal values of the first derivative of left ventricular pressure (dP/dt) were significantly improved in ROSI-treated rats. ROSI reduced the accumulation of neutrophils and macrophages in the ischemic heart by 40% and 43%, respectively (P<0.01). Ischemia/reperfusion induced upregulation of CD11b/CD18 and downregulation of L-selectin on neutrophils and monocytes; these effects were significantly attenuated in ROSI-treated animals. Likewise, intercellular adhesion molecule-1 expression in ischemic hearts was markedly diminished by ROSI, as was the ischemia/reperfusion-stimulated upregulation of monocyte chemoattractant protein-1.
Conclusions ROSI reduced myocardial infarction and improved contractile dysfunction caused by ischemia/reperfusion injury. The cardioprotective effect of ROSI was most likely due to inhibition of the inflammatory response.
Key Words: ischemia • myocardial infarction • diabetes • PPAR-
• rosiglitazone
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