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.