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 S1PR1-5. 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.

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases

“…Overall, these observations may reveal S1P/S1PR-specific cardioprotective mechanisms in regulating cardiac physiology, and hence offer novel therapeutic strategies by targeting this axis (Section 7). However, the specific S1PRs involved in cardioprotective effects have not yet been dissected, with compelling evidence potentially suggesting that S1PR1, S1PR2, and S1PR3 might work together [69].…”

Overexpression of Sphingosine Kinase-1 and Sphingosine-1-Phosphate Receptor-3 in Severe Plasmodium falciparum Malaria with Pulmonary Edema

“…S1P performs diverse functions, which are mediated in a receptor-dependent manner through G protein-coupled receptors (S1PR-1-S1PR-5) [19]. In mammals, S1P receptors are widely expressed and are believed to play a role in important physiological processes, such as immune cell trafficking, vascular development, vascular tone control, cardiac function, and vascular permeability [13,20]. A previous study demonstrated that the action of S1P through S1PR-1 receptor contributed to a barrier-protective effect by increasing cortical actin, which promotes adherens junction and focal adhesion complex formation and stabilization [10].…”

The role of sphingolipids in cardiovascular pathologies

“…У пациентов, перенесших инфаркт миокарда, снижался уровень С-1-Ф в крови [49,50]. На модели ишемии у крыс и мышей также было получено снижение уровня С-1-Ф как в сердечной мышце, так и в крови по сравнению с контрольными животными [51,52]. Кроме того, обнаружено резкое (в 3 раза) снижение С-1-Ф в неинфарктной зоне миокарда крыс Wistar при моделируемом инфаркте.…”