TNFα-Mediated Down-Regulation of CFTR Drives Pathological S1P Signaling in a Mouse Model of Heart Failure
Background—Sphingosine-1-phosphate (S1P) signaling is a central regulator of resistance artery tone. Therefore, S1P levels need to be tightly controlled through the delicate interplay of its generating enzyme sphingosine kinase 1, and its functional antagonist, S1P phosphohydrolase 1 (SPP1). The intracellular localization of SPP1 necessitates the import of extracellular S1P into the intracellular compartment prior to its degradation. The present investigation proposes that the cystic fibrosis transmembrane regulator (CFTR) transports extracellular S1P and hence, modulates microvascular S1P signaling in health and disease.
Methods and Results—In cultured murine vascular smooth muscle cells in vitro and isolated murine mesenteric and posterior cerebral resistance arteries ex vivo, CFTR (i) is critical for S1P uptake; (ii) modulates S1P-dependent responses; and (iii) is down-regulated in vitro and in vivo by TNFα, with significant functional consequences for S1P signaling and vascular tone. In heart failure, TNFα down regulates CFTR across several organs, including the heart, lung and brain, suggesting that it is a fundamental mechanism, with implications for systemic S1P effects.
Conclusions—We identify CFTR as a critical regulatory site for S1P signaling; its TNFα-dependent down-regulation in heart failure underlies an enhancement in microvascular tone. This molecular mechanism potentially represents a novel and highly-strategic therapeutic target for cardiovascular conditions involving inflammation.
- Received June 3, 2011.
- Accepted March 20, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited