title: Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2.
abstract: Our previous study demonstrated that the peroxisome proliferator-activated receptor (PPAR) γ agonist, pioglitazone (PIO), may be cardioprotective against ischemia-reperfusion injury; however, modulation of p42/p44 extracellular signal-regulated kinases (ERK1/2) and cyclooxygenase (COX)-2 by PIO in the myocardium with respect to ischemia-reperfusion (I/R) is only partially understood. We determined if PIO reduces I/R-induced apoptosis in cardiomyocytes, and whether or not this protective effect is due to modulation of ERK1/2 and COX-2. Sixty male Sprague-Dawley rats were randomized and assigned to 1 of 6 groups: I/R; I/R + PIO (5 mg•kg(-1)•day(-1)); I/R + PIO (10 mg•kg(-1)•day(-1)); I/R + PIO (10 mg•kg(-1)•day(-1)) + the ERK1/2 inhibitor, PD98059; I/R + PIO ( 10 mg•kg(-1)•day(-1)) + GW9662;and I/R + PD98059. Rats underwent 30 min of myocardial ischemia and 120 min of reperfusion, and then hearts were harvested for analysis. RT-PCR and Western blotting were performed to detect expression of ERK1/2 and COX-2. The number of TUNEL-positive cardiomyocytes and NEC in the PIO groups (5 and 10 mg•kg(-1)•day(-1)) was much lower than the I/R group. The cardioprotective effect of PIO was abrogated by PD98059 and GW9662. Phosphorylation of ERK1/2 and COX-2 was increased in the PIO-treated group compared with the I/R group. GW9662 reversed the expression of ERK1/2 and COX- 2 phosphorylation induced by PIO. PD98059 reversed the expression of COX-2 induced by PIO. PIO was shown to be cardioprotective in an I/R injury model in rats via inhibition of cardiomyocyte apoptosis. PIO limited the infarct size in a PPAR-γ-dependent manner. These results show that PIO triggers the MAPK signaling pathway involving ERK1/2 using COX-2 as the downstream target.
authors: Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China.
authors: H
authors: H
authors: Wang
authors: Q W
authors: QW
authors: Zhu
authors: P
authors: P
authors: Ye
authors: Z B
authors: ZB
authors: Li
authors: Y
authors: Y
authors: Li
authors: Z L
authors: ZL
authors: Cao
authors: L
authors: L
authors: Shen
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D005419:Flavonoids; D045162:Thiazolidinediones; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077205:Pioglitazone