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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/H719    most recent 00394.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bulhak, A. A. Articles by Pernow, J. Search for Related Content PubMed PubMed Citation Articles by Bulhak, A. A. Articles by Pernow, J.

PPAR- activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

¹Division of Cardiology, Department of Medicine, ²Endocrine and Diabetes Unit, Department of Molecular Medicine and Surgery, The Rolf Luft Center for Diabetes Research, Karolinska University Hospital, and ³Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

Submitted 15 April 2008 ; accepted in final form 7 January 2009

Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferator-activated receptor- (PPAR-) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR- would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and age-matched Wistar rats (n 7) were given either 1) the PPAR- agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor N^G-nitro-L-arginine (L-NNA), 4) L-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/nitrate were determined. The IS was 75 ± 3% and 72 ± 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 ± 3% in Wistar (P < 0.05) and to 46 ± 5% in GK rats (P < 0.001). The addition of either L-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 ± 5% and 65 ± 5%, respectively) and GK (IS, 66 ± 4% and 64 ± 4%, P < 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats (P < 0.05). The results suggest that PPAR- activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.

peroxisome proliferator-activated receptor- ligand; endothelial function; phosphatidylinositol 3-kinase