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

Abstract

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)-gamma 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-gamma, 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.

miRNA-711-SP1-collagen-I pathway is involved in the anti-fibrotic effect of pioglitazone in myocardial infarction

“…Pioglitazone has been reported to attenuate cardiac fibrosis and improve left ventricular failure [4][5][6]. The current study also demonstrated that pioglitazone inhibited collagen-I expression ( Figure 1C) and ameliorated cardiac fibrosis in myocardial infarction hearts ( Figure 1A and B).…”

“…It attenuated cardiac fibrosis, improved left ventricular failure and reduced myocardial infarct size after experimental MI [4][5][6].…”

Nitro-Oleic Acid Attenuates OGD/R-Triggered Apoptosis in Renal Tubular Cells via Inhibition of Bax Mitochondrial Translocation in a PPAR-γ-Dependent Manner

“…The protective role of PPAR-γ in I/R injury is suggested by data showing that heterozygous PPAR-γ-deficient mice subjected to intestinal I/R suffer more pronounced injury than wild-type control mice [6] and that the PPAR-γ agonist, rosiglitazone, is able to control cell apoptosis and contribute to tissue protection [7,8,9]. Therefore, agents that regulate PPAR-γ activation are being actively pursued.…”

Biogenesis and Regulation of Cardiovascular MicroRNAs

“…Treatment with the antidiabetic peroxisome proliferatoractivated receptor (PPAR)-gamma agonist pioglitazone reduced myocardial infarct size, but the exact mechanism has not been elucidated. 110 Pioglitazone treatment resulted in cardiac down-regulation of miR-29a and miR-29c levels. In line, antagomirs against miR-29a or miR-29c reduced myocardial infarct size as well as apoptosis in hearts subjected to ischemia-reperfusion injury by targeting the antiapoptotic Bcl2 member Mcl-1.…”