The Role of TNFα and Sphingolipid Signaling in Cardiac Hypoxia: Evidence that Cardiomyocytes Release TNFα and Sphingosine

Abstract

Sphingosine (SPH) is a naturally occurring signaling molecule thought to be responsible for the negative inotropic and cardiotoxic effects of the pro-inflammatory cytokine, TNFα. When subjected to hypoxia and acidosis, Langendorff perfused adult rabbit hearts generate SPH, and isolated adult rat cardiomyocytes released TNFα and SPH into the cell-conditioned media under hypoxic conditions before hypoxia-induced cell permeabilization associated with necrosis. Cardiomyocyte SPH production in response to hypoxia was blocked by TNFRII:Fc which interferes with TNFα binding to its membrane-bound receptor, suggesting that hypoxiatriggered SPH production was TNFα dependent. Extracellular SPH was rapidly converted almost exclusively to S1P by an active sphingosine kinase present in blood components, as seen in vitro and in Langendorff-perfused rat hearts. These results indicate that cardiacderived TNFα and its sphingolipid mediator, SPH, may be important extracellular signals in the heart that contribute to the pathogenesis of cardiac ischemia