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Review
. 2020 Sep;24(18):10290-10301.
doi: 10.1111/jcmm.15744. Epub 2020 Aug 17.

The role of sphingosine 1-phosphate and its receptors in cardiovascular diseases

Jie Ouyang  1   2 , Zhihao Shu  2 , Shuhua Chen  3 , Hong Xiang  1 , Hongwei Lu  1   2
Affiliations
Review

The role of sphingosine 1-phosphate and its receptors in cardiovascular diseases

Jie Ouyang et al. J Cell Mol Med. 2020 Sep.

Abstract

There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator with paracrine and autocrine activities that acts through its cell surface S1P receptors (S1PRs) and intracellular signals. In the circulatory system, S1P is indispensable for both normal and disease conditions; however, there are very different views on its diverse roles, and its specific relevance to cardiovascular pathogenesis remains elusive. Here, we review the synthesis, release and functions of S1P, specifically detail the roles of S1P and S1PRs in some common cardiovascular diseases, and then address several controversial points, finally, we focus on the development of S1P-based therapeutic approaches in cardiovascular diseases, such as the selective S1PR1 modulator amiselimod (MT-1303) and the non-selective S1PR1 and S1PR3 agonist fingolimod, which may provide valuable insights into potential therapeutic strategies for cardiovascular diseases.

Keywords: cardiovascular disease; sphingosine 1-phosphate; sphingosine 1-phosphate receptor.

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Conflict of interest statement

The authors confirm that there are no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
The biosynthesis and secretion of S1P. ECs, endothelial cells; ER, endoplasmic reticulum; LPP, lipid phosphatase; RBCs, red blood cells; S1P, sphingosine 1‐phosphate; S1PL, S1P lyase; S1PRs, sphingosine 1‐phosphate receptors; Sgpp, S1P phosphatase; Sphk, sphingosine kinase; Spns2, spinster‐2 transporter
FIGURE 2
FIGURE 2
Differential effects of S1PRs at different stages after myocardial infarction. A, A protective effect of S1P in myocardial infarction in the early stage. B, A damaging effect of S1P in myocardial infarction in the late stage. EF, ejection fraction; LVEF, left ventricular ejection fraction; LVFS, left ventricular fraction shortening; LVID, left ventricular internal dimension; Meto, metoprolol; S1PR, sphingosine 1‐phosphate receptor
FIGURE 3
FIGURE 3
S1PR2 participates in endothelial mitochondrial apoptosis and dysfunction. A, S1PR2 antagonist inhibits HG‐induced cell apoptosis. After 1 h of exposure to 1 mmol/L JTE‐013, HUVECs were treated with normal glucose, high mannitol and high glucose for 72 h. *P < 0.05 vs the control group. # P < 0.05 vs the HG group. B, S1PR1 reduces, but S1PR2 enhances hyperglycaemia‐induced oxidative stress and morphogenetic response in HUVECs. The cells were transfected with either pAd‐S1PR1 or shRNA‐S1PR2 for overexpressing S1PR1 and silencing S1PR2, respectively. *, # P < 0.05 vs the HG group. Adopted with permission from Ref.54, 55 HG, high glucose; Mnt, mannitol
FIGURE 4
FIGURE 4
The multifaceted role of S1P in atherosclerosis. A, HDL‐S1P has anti‐atherosclerotic and anti‐inflammatory effects and inhibits macrophage apoptosis. B, S1P promotes endothelial progenitor cells (EPCs) proliferation, reduces EPCs and macrophages apoptosis, and enhances cholesterol efflux. C, Albumin‐bound S1P has atherosclerotic effect through S1PR2. iNOS, inducible NO synthase; MMP9, matrix metalloproteinase 9; PAI‐1, plasminogen activator inhibitor 1
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