Abstract
Sphingosine-1-phosphate (S1P) is a pleiotropic lysophospholipid mediator that acts on 5 members of the G protein-coupled S1P receptor family to induce diverse biological responses. S1P1, S1P2 and S1P3, which are widely expressed receptor subtypes, exert distinct regulatory effects on cytoarchitecture, cell migration, proliferation and gene expression, through differential coupling to heterotrimeric G proteins and downstream signaling, including activation of Rac and Rho small GTPases. Recent studies indicate the involvement of the S1P signaling system in inflammation and fibrosis. Investigations into genetically engineered mice have provided evidence that S1P2 and S1P3 receptors, together with sphingosine kinase 1 (SphK1), which is a major S1P synthesizing enzyme, participate in fibrogenic processes, through mechanisms involving activation of the Rho-dependent pathway and cross-talk with TGFβ signaling. This review will focus on the basics of the S1P signaling system, which include S1P receptor subtype-specific signaling and biological activities, production and degradation of S1P, and currently available in vivo data, including our own data, regarding how S1P signaling is involved in cardiac fibrosis, a pathological feature of cardiac remodeling that leads to chronic heart failure, which is one of leading causes of death in developed countries.
