Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKCε knockout mouse hearts

Abstract

Sphingosine-1-phosphate (S1P) protects neonatal rat cardiac myocytes from hypoxic damage through unknown signaling pathways. We tested the hypothesis that S1P-induced cardioprotection requires activation by the ε-isoform of protein kinase C (PKCε) by subjecting hearts isolated from PKCε knockout mice and wild-type mice to 20 min of global ischemia and 30 min of reperfusion. Pretreatment with a 2-min infusion of 10 nM S1P improved recovery of left ventricular developed pressure (LVDP) in both wild-type and PKCε knockout hearts and reduced the rise in LV end-diastolic pressure (LVEDP) and creatine kinase (CK) release. Pretreatment for 2 min with 10 nM of the ganglioside GM-1 also improved recovery of LVDP and suppressed CK release in wild-type hearts but not in PKCε knockout hearts. Importantly, GM-1 but not S1P, increased the proportion of PKCε localized to particulate fractions. Our results suggest that GM-1, which enhances endogenous S1P production, reduces cardiac injury through PKCε-dependent intracellular pathways. In contrast, extracellular S1P induces equivalent cardioprotection through PKCε-independent signaling pathways.