Globular adiponectin attenuates myocardial ischemia/reperfusion injury by upregulating endoplasmic reticulum Ca²âº-ATPase activity and inhibiting endoplasmic reticulum stress.

ABSTRACT

AIM: The aim of this study was to explore the mechanisms underlying the effects of globular adiponectin (gAd) on myocardial ischemia/reperfusion (I/R) injury. METHODS: An in vivo myocardial I/R model and an in vitro neonatal rat cardiomyocyte hypoxia/reoxygenation (H/R) model simulating I/R injury in vivo were adopted to investigate whether and how the cardioprotective effects of gAd are mediated by the inhibition of endoplasmic reticulum (ER) stress. RESULTS: gAd (1 µg/g, intravenously) attenuated the myocardial infarct size, myocardial enzyme activity, and apoptosis in rats with I/R, and similar protection was observed in primary cultures of neonatal rat cardiomyocytes. The protective effects of gAd were associated with the suppression of ER stress, as evidenced by reversing the upregulation of 78-kDa glucose-regulated protein, C/EBP homologous protein, and caspase-12 that were induced by H/R and thapsigargin. In addition, gAd conferred resistance to ER stress and cardiomyocyte injury by modulating ER Ca²âº-ATPase (SERCA) activity. Moreover, gAd further increased H/R-enhanced Akt phosphorylation. The protective effects of gAd on ER stress and SERCA activity were abolished by preincubation of rat neonatal cardiomyocytes with the PI3K inhibitor LY294002. Consistent with this finding, I/R-induced ER stress and SERCA dysfunction were also significantly ameliorated by gAd. These effects involved PI3K/Akt signaling pathway. CONCLUSIONS: The protective effects of gAd during I/R are mediated, at least in part, by modulating SERCA activity and consequently suppressing ER stress via the activation of PI3K/Akt signaling.