Sphingosine Kinases and Sphingosine 1-Phosphate Receptors: Signaling and Actions in the Cardiovascular System

Abstract

The sphingosine kinases 1 and 2 (SphK1 and 2) catalyze the phosphorylation of the lipid, sphingosine, generating the signal transmitter, sphingosine 1-phosphate (S1P). The activation of such kinases and the subsequent S1P generation and secretion in the blood serum of mammals represent a major checkpoint in many cellular signaling cascades. In fact, activating the SphK/S1P system is critical for cell motility and proliferation, cytoskeletal organization, cell growth, survival, and response to stress. In the cardiovascular system, the physiological effects of S1P intervene through the binding and activation of a family of five highly selective G protein-coupled receptors, called S1PR_1-5. Importantly, SphK/S1P signal is present on both vascular and myocardial cells. S1P is a well-recognized survival factor in many tissues. Therefore, it is not surprising that the last two decades have seen a flourishing of interest and investigative efforts directed to obtain additional mechanistic insights into the signaling, as well as the biological activity of this phospholipid, and of its receptors, especially in the cardiovascular system. Here, we will provide an up-to-date account on the structure and function of sphingosine kinases, discussing the generation, release, and function of S1P. Keeping the bull's eye on the cardiovascular system, we will review the structure and signaling cascades and biological actions emanating from the stimulation of different S1P receptors. We will end this article with a summary of the most recent, experimental and clinical observations targeting S1PRs and SphKs as possible new therapeutic avenues for cardiovascular disorders, such as heart failure.

Keywords: G protein-coupled receptors; cardiovascular; fingolimod; gene-therapy; heart failure; sphingosine 1-phosphate; sphingosine kinase.

FIGURE 1

Schematic representation of S1PRs signaling activation in the cardiovascular system. Ceramide is catabolized by ceramidase to produce sphingosine that, in turn, is phosphorylated by sphingosine kinases 1 and 2 (SphK1 and 2) to generate the sphingosine 1-phosphate (S1P). Cellular S1P concentrations are regulated by the balance between its synthesis and de-phosphorylation mediated by S1P phosphatases (SPP). In the cytosol, S1P can also be irreversibly cleaved into trans-2-hexadecenal and ethanolamine phosphate or can be exported out of cells through the “inside-out” mechanism where it can bind three different receptors (S1PR_1-3). Activation of S1PR₁ induces negative inotropic effects via G protein (Gi) activation and decreased cAMP concentration. Moreover, S1PR₁ is able to positively affect endothelial function and to confer protection to the heart, via activation of the mitogen-activated protein kinase 1 and 2 (ERK) and the protein kinase B (Akt). Both S1PR₂ and S1PR₃ activate Gi, Gq, and G12/13 appear to collaborate in providing cardioprotection and in regulating cardiac hypertrophy. However, while S1PR₂ is involved in endothelial dysfunction and promotion of fibroblasts function, S1PR₃ appears to influence the vascular tone and induce bradycardia.

FIGURE 2

Cardiac effects associated with Fingolimod-mediated activation of S1PR₁ and S1PR₃. Fingolimod is phosphorylated by sphingosine kinase 2 (SphK2) to generate Fingolimod-phosphate (Fingolimod) that in turn binds to S1PR₁. However, the sustained stimulation leads to S1PR₁ internalization and degradation and to sphingosine kinase 1 (SphK1) inhibition. These effects are probably related to an impairment of the function of the left ventricle (LV). Moreover, via binding and activation of S1PR₃, Fingolimod can induce bradycardia.