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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/H1558    most recent 00712.2008v1 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 Yasuda, S. Articles by Minatoguchi, S. Search for Related Content PubMed PubMed Citation Articles by Yasuda, S. Articles by Minatoguchi, S.

Antidiabetic drug pioglitazone protects the heart via activation of PPAR- receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction

¹Department of Cardiology, Gifu University Graduate School of Medicine, Yanagido, Gifu; ²Kyoto Women's University, Kyoto; and ³Amagasaki Prefectural Hospital, Japan

Submitted 10 July 2008 ; accepted in final form 13 February 2009

The insulin-sensitizing drug pioglitazone has been reported to be protective against myocardial infarction. However, its precise mechanism is unclear. Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Rabbits were assigned randomly to nine groups (n = 10 in each): the control group (fed a normal diet), pioglitazone group (fed diets containing 1 mg·kg^–1·day^–1 pioglitazone), pioglitazone + 5-hydroxydecanoic acid (HD) group [fed the pioglitazone diet + 5 mg/kg iv 5-HD, a mitochondrial ATP-sensitive K⁺ (K_ATP) channel blocker], pioglitazone + GW9662 group [fed the pioglitazone diet + 2 mg/kg iv GW9662, a peroxisome proliferator activated receptor (PPAR)- antagonist], GW9662 group (fed a normal diet + iv GW9662), pioglitazone + wortmannin group [fed the pioglitazone diet + 0.6 mg/kg iv wortmannin, a phosphatidylinositol (PI)3-kinase inhibitor], wortmannin group (fed a normal diet + iv wortmannin), pioglitazone + nitro-L-arginine methyl ester (L-NAME) group [fed the pioglitazone diet + 10 mg/kg iv L-NAME, a nitric oxide synthase (NOS) inhibitor], and L-NAME group (fed a normal diet + iv L-NAME). All groups were fed the diets for 7 days. The risk area and nonrisk area of the left ventricle (LV) were separated by Evans blue dye, and the infarct area was determined by triphenyltetrazolium chloride staining. The infarct size was calculated as a percentage of the LV risk area. Western blotting was performed to assess levels of Akt and phospho-Akt and phospho-endothelial NOS (eNOS) in the myocardium following reperfusion. The infarct size was significantly smaller in the pioglitazone group (21 ± 2%) than in the control group (43 ± 3%). This effect was abolished by GW9662 (42 ± 3%), wortmannin (40 ± 3%), or L-NAME (42 ± 7%) but not by 5-HD (24 ± 5%). Western blotting showed higher levels of phospho-Akt and phospho-eNOS in the pioglitazone group. Pioglitazone reduces the myocardial infarct size via activation of PPAR-, PI3-kinase, Akt, and eNOS pathways, but not via opening the mitochondrial K_ATP channel. Pioglitazone may be a novel strategy for the treatment of diabetes mellitus with coronary artery disease.

peroxisome proliferator activated receptor-; phosphatidylinositol 3-kinase; endothelial nitric oxide synthase; infarct size; diabetes mellitus; ischemia-reperfusion