Abstract 17708: Adiponectin Cardioprotection in Myocardial Ischemia/Reperfusion Involves Sphingosine 1-Phosphate-Dependent Activation of Sarcoplasmic Reticulum PLB-SERCA2a
Introduction: Sphingosine 1-phosphate (S1P) is an effective cardioprotectant against ischemic injury. Recent study indicates that adiponectin mediates conversion of ceramides into S1P. However, whether S1P is cardioprotective or a mediator of adiponectin cardioprotection remains unknown.
Methods and Results: Male adult C57BL/6J mice were subjected to 30 minutes of myocardial ischemia followed by 30 minutes [for CaMKIIThr286, PLBSer16 and PLBThr17 phosphorylation and sarcoplasmic reticulum (SR) SERCA2a activity], 3 hours (for apoptosis) or 24 hours (for cardiac function) of reperfusion and treated with vehicle, adiponectin or adiponectin plus VPC23019 (VPC, a speci[[Unable to Display Character: ﬁ]]c S1P1/3 receptors antagonist). Administration of adiponectin 20 min before reperfusion increased CaMKIIThr286, PLBSer16 and PLBThr17 phosphorylation and SR SERCA2a activity, reduced apoptosis and improved cardiac function (all P<0.05). Pretreatment with VPC virtually abolished adiponectin’s effects (all P<0.05). Moreover, adiponectin significantly increased plasma S1P level at 30 minutes of reperfusion (P<0.05). In cultured neonatal rat ventricular myocytes, hypoxia/reoxygenation (1.5h/1.5h) induced reduction of CaMKIIThr286, PLBSer16 and PLBThr17 phosphorylation and SR SERCA2a activity. Treatment with S1P (1μ M) or adiponectin (3μ g/mL) reversed these alterations, increased cell viability, reduced LDH release and TUNEL-positive myocytes (all P<0.01). However, pretreatment with VPC abolished S1P and adiponectin’s effects (all P<0.05). Moreover, pretreatment with Rp-cAMP (PKA inhibitor), KN-93 (CaMKII inhibitor) or two different PLB siRNAs also partially abolished the cardioprotection of S1P and adiponectin (all P<0.05).
Conclusions: The present study demonstrates that adiponectin exerts its cardioprotective effects partially through S1P-dependnet, PKA and CaMKII-mediated SR PLB-SERCA2a activation.
- © 2012 by American Heart Association, Inc.