Adiponectin regulates SR Ca2+ cycling following ischemia/reperfusion via sphingosine 1-phosphate-CaMKII signaling in mice

The adipocyte-secreted hormone adiponectin (APN) exerts protective effects on the heart under stress conditions. Recent studies have demonstrated that APN induces a marked Ca2+ influx in skeletal muscle. However, whether APN modulates [Ca2+](i) activity, especially [Ca2+](i) transients in cardiomyocytes, is still unknown. This study was designed to determine whether APN modulates [Ca2+](i) transients in cardiomyocytes. Adult male wild-type (WT) and APN knockout (APN KO) mice were subjected to myocardial ischemia/reperfusion (I/R, 30 min/30 min) injury. CaMKII-PLB phosphorylation and SR Ca2+-ATPase (SERCA2) activity were downregulated in I/R hearts of WF mice and further decreased in those of APN KO mice. Both the globular domain of APN and full-length APN significantly reversed the decrease in CaMKII-PLB phosphorylation and SERCA2 activity in WT and APN KO mice. Interestingly, compared with WT littermates, single myocytes isolated from APN KO mice had remarkably decreased [Ca2+](i) transients, cell shortening, and a prolonged Ca2+ decay rate. Further examination revealed that APN enhances SERCA2 activity via CaMKII-PLB signaling. In in vivo and in vitro experiments, both APN receptor 1/2 and SIP were necessary for the APN-stimulated CaMKII-PLB-SERCA2 activation. In addition, SIP activated CaMKII-PLB signaling in neonatal cardiomyocytes in a dose dependent manner and improved [Ca2+](i) transients in APN KO myocytes via the SIP receptor (S1PR1/3). Further in vivo experiments revealed that pharmacological inhibition of S1PR1/3 and SERCA2 siRNA suppressed APN-mediated cardioprotection during I/R. These data demonstrate that SIP is a novel regulator of SERCA2 that activates CaMKII-PLB signaling and mediates APN-induced cardioprotection. (C) 2014 Elsevier Ltd. All rights reserved.