Sphingosine 1-phosphate as a therapeutic target in heart failure: more questions than answers.

Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive lysophospholipid that regulates immune responses and inflammatory processes in a variety of different organ systems, including the cardiovascular system. Within the cardiovascular system, S1P mediates cardioprotection following ischemia/reperfusion injury, cardiac remodeling, vascular tone, angiogenesis, and fibroblast migration, proliferation, and differentiation, as well.1 In the current issue of Circulation, Meissner and colleagues present novel findings in a murine heart failure model (left anterior descending artery ligation) which suggest that S1P activity is modulated by a cAMP-responsive chloride channel termed the cystic fibrosis transmembrane regulator (CFTR).2 CFTR, a member of the ATP-binding cassette family of genes, was identified as the gene responsible for the loss of chloride secretion in patients with cystic fibrosis. Based on a previous report by the same group,3 which showed that the intracellular enzyme S1P phosphohydrolase that degrades extracellular S1P, was also an endogenous regulator of S1P-mediated vasoconstriction, the authors hypothesized that S1P must be imported by vascular smooth muscle cells. In their current report, Meissner et al show that CFTR mRNA was present in conduit and resistance arteries throughout the vascular tree in mice. They further noted that CFTR was required for S1P uptake by vascular smooth muscle cells, and that vascular smooth muscle cells from wild-type (CFTR / ) possessed a higher rate of proliferation than vascular smooth muscle cells from CFTR null (CFTR / ) mice, consistent with the known antiproliferative effects of S1P on vascular smooth muscle cells. At the whole organ level, S1P-mediated vasoconstriction of small resistance arteries (eg, the posterior cerebral artery) was more potent in CFTR / than in CFTR / mice, whereas the vasoconstrictor response to phenylephrine and the vasodilator response to acetylcholine did not differ between CFTR / and CFTR / mice. Finally the authors showed that CFTR mRNA levels were decreased in resistance vessels of wild-type mice that had undergone acute left anterior descending artery ligation, suggesting that decreased uptake of S1P of CFTR resulted in sustained S1P signaling and enhanced vascular tone. The authors further made the interesting observation that CFTR mRNA levels were downregulated by tumor necrosis factor, a proinflammatory cytokine that is increased in heart failure,4 and that treatment with etanercept, a tumor necrosis factor antagonist,5 rescued many aspects of the heart failure phenotype, including normalization of vascular tone, and downregulation of CFTR, as well. Given that the CFTR downregulation was reversible and that increased peripheral vasoconstriction contributes to disease progression in heart failure, Meissner et al suggest that CFTR may represent a novel target for cardiovascular conditions such as heart failure wherein inflammation is present. Before addressing this interesting question, it is instructive to first review S1P signaling within the cardiovascular system.