Pioglitazone limits myocardial infarct size, activates Akt, and upregulates cPLA2 and COX-2 in a PPAR-c-independent manner
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Yochai Birnbaum Bo Long Jinqiao Qian Jose R. Perez-Polo Yumei Ye
- چاپ و سال / کشور: 2011
Description
Pioglitazone (PIO), a PPAR-c agonist, limits myocardial infarct size by activating Akt and upregulating cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX)-2. However, PIO has several PPAR-c-independent effects. We assessed whether PIO limits myocardial infarct size in PPAR-c–knockout mice, attenuates hypoxiareoxygenation injury and upregulates P-Akt, cPLA2, and COX-2 expression in PPAR-c–knockout cardiomyocytes. Cardiac-specific inducible PPAR-c knockout mice were generated by crossing aMHC-Cre mice to PPAR-cloxp/loxp mice. PPAR-c deletion was achieved after 7 days of intraperitoneal tamoxifen (20 mg/kg/day) administration. Mice received PIO (10 mg/kg/day), or vehicle, for 3 days and underwent coronary occlusion (30 min) followed by reperfusion (4 h). We assessed the area at risk by blue dye and infarct size by TTC. Cultured adult cardiomyocytes of PPAR-cloxp/loxp/cre mice without or with pretreatment with tamoxifen were incubated with or without PIO and subjected to 2 h hypoxia/2 h reoxygenation. Cardiac-specific PPAR-c knockout significantly increased infarct size. PIO reduced infarct size by 51% in PPAR-c knockout mice and by 55% in mice with intact PPAR-c. Deleting the PPAR-c gene increased cell death in vitro. PIO reduced cell death in cells with and without intact PPAR-c. PIO similarly increased myocardial Ser-473 P-Akt, cPLA2, and COX-2 levels after hypoxia/reoxygenation in cells with and without intact PPAR-c. PIO limited infarct size in mice in a PPAR-c-independent manner. PIO activated Akt, increased the expression of cPLA2 and COX-2, and protected adult cardiomyocytes against the effects of hypoxia/reoxygenation independent of PPAR-c activation
Basic Res Cardiol (2011) 106:431–446 Received: 26 July 2010 / Revised: 1 February 2011 / Accepted: 4 February 2011 / Published online: 1 March 2011
