title: Resistin, an adipocytokine, offers protection against acute myocardial infarction.
abstract: Resistin, an adipocyte-derived hormone, is thought to represent a link between obesity and insulin-resistant diabetes. The potential role of resistin as a cardioprotective agent has not been explored. Our hypothesis is that resistin has a cardioprotective effect that is mediated by the resistin receptor-coupled activation of PI3K/Akt/PKC/K(ATP) dependent pathways. Our studies demonstrated that pretreatment of mouse hearts with 10 nM resistin for 5 min protected the heart against I/R injury in a mouse heart perfusion model. When mouse hearts were subjected to 60 min of LAD ligation followed by 4 h of reperfusion, resistin pretreatment (33 microg/kg) for 30 min or 24 h before ligation was able to significantly reduce the infarct size/risk area. The protective effect of resistin was abolished by wortmannin, as well as by an Akt inhibitor, triciribine. Resistin's protective effect was absent in Akt kinase-deficient mutant mice. The protective effect was also blocked by chelerythrine, a PKC inhibitor, and epsilonV1-2, a PKCepsilon inhibitor. Finally, the protective effect was blocked by 5-hydroxydecanoate, which blocks the opening of mitoK(ATP) channels. Resistin-induced Akt phosphorylation in HL-1 cells was inhibited by wortmannin and triciribine. Resistin also induced PKCepsilon phosphorylation, which was blocked by triciribine. These studies demonstrate that resistin's cardioprotective effect is mediated by PI3K/Akt/PKC dependent pathways. In addition to cardiomyocytes, resistin also induced Akt phosphorylation in endothelial cells and smooth muscle cells, suggesting that resistin receptors are present in these cells. The effect of resistin on apoptosis was assessed in hearts subjected to 30 min of ischemia and 3 h of reperfusion. There were significantly fewer in situ oligo ligation-positive myocyte nuclei in mice treated with resistin. Our results show that resistin can dramatically reduce apoptosis and infarct size, thus protecting the heart against I/R injury.
authors: Cecile Cox Quillen Laboratory of Geriatrics, James H. Quillen College of Medicine East Tennessee State University, and James H. Quillen Veterans Affairs Medical Center, Johnson City, TN 37614, USA.
authors: Jinping
authors: J
authors: Gao
authors: Chu
authors: C
authors: Chang Chua
authors: Zhongyi
authors: Z
authors: Chen
authors: Hong
authors: H
authors: Wang
authors: Xingshun
authors: X
authors: Xu
authors: Ronald
authors: R
authors: C Hamdy
authors: Julie R
authors: JR
authors: McMullen
authors: Tetsuo
authors: T
authors: Shioi
authors: Seigo
authors: S
authors: Izumo
authors: Balvin H L
authors: BH
authors: Chua
mesh_terms: D054392:Adipokines / Q000627:therapeutic use; D000730:Androstadienes / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology; D006352:Heart Ventricles / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000517:prevention & control; D052243:Resistin / Q000502:physiology / Q000627:therapeutic use*; D012263:Ribonucleosides / Q000627:therapeutic use; D000077191:Wortmannin
chemical_list: D054392:Adipokines; D000730:Androstadienes; D052243:Resistin; D012263:Ribonucleosides; C023764:triciribine; D000077191:Wortmannin