ReviewSphingosine 1-phosphate and its receptors in ischemia
Introduction
Atherosclerosis is a systemic pathological change initiated by endothelial dysfunction for inflammation and high levels of low-density lipoprotein (LDL), and then accompanied by deposition of lipids and the formation of plaques on arterial walls. Atherosclerosis generally leads to arterial lumen stenosis, and in some cases ruptured plaques form thrombus, thus leading to partial or total occlusion of the artery, interruption of blood flow and ischemia [1], [2]. Hence, the main clinical manifestations of atherosclerosis include myocardial infarction (MI), ischemic stroke, and peripheral artery disease [3]. Atherosclerotic lesions in the coronary arteries lead to MI, which ultimately leads to impaired cardiac function [4]. In turn, MI accelerates atherosclerosis by recruiting monocytes [5]. Cerebral infarction, also known as ischemic stroke, is another high-incidence infarction disease in people with atherosclerosis. Patients may suffer from mobility impairment, dysfunction of consciousness and language for stroke. Cerebral infarction often occurs in the middle cerebral artery, the proximal internal carotid artery and the basilar artery [6]. Since ischemia is a state of tissues or organs with temporary interruption of blood flow, restoring blood supply is one of the main therapeutic methods. However, reperfusion therapy potentially aggravates injury for too much free radical production and intracellular calcium overload which will both can induce the apoptosis of cells and cause ischemia–reperfusion (I/R) injury. Therefore, it is imperative to seek new therapeutic approaches.
Sphingosine 1-phosphate (S1P) is a sphingomyelin metabolite mainly derived from red blood cells (RBCs), platelets and endothelial cells (ECs). Besides action inside cells as a signaling molecule to regulate specific targets involved in fibroblasts, mitochondrial assembly and inflammation et al [7], S1P can be exported out of the cell acts as ligand of sphingosine 1-phosphate receptors (S1PRs) which was initially named as endothelial differentiation genes (EDGs) and plays a variety of biological functions such as angiogenesis and immune regulation [8]. Meanwhile, it also plays a crucial part in a variety of pathological conditions such as atherosclerosis, diabetes and cancer [9], [10]. In addition, the S1P signaling pathway interferes in ischemic damage of tissues or organs by controlling inflammation and cell apoptosis [11]. Activation of S1PR1 with specific agonists was reported to delay the development of atherosclerosis [12], [13]. Fingolimod (FTY720), an S1PRs non-specific agonist (except for S1PR2), was reported to inhibit the cardiomyocyte apoptosis on the ischemic border zone, thus reducing the infarction area in a porcine model of I/R [14]. Similarly, activation of S1PR1 with agonists could attenuate pulmonary I/R injury by reducing the expression of pro-inflammatory factors and neutrophil infiltration [15]. These results suggested the close relationship between S1P/S1PRs and atherosclerosis as well as ischemia, and may provide ideas for potential targets for the intervention of atherosclerosis and ischemia. This review focuses on the role of S1PRs in regulation of atherosclerosis and subsequent MI and ischemic stroke.
Section snippets
Atherosclerosis and ischemic diseases
Atherosclerosis is a chronic inflammatory disease based on lipid metabolism disorder and characterized by the formation of atherosclerotic plaques. Unhealthy lifestyle, genetic factors, aging, and disorders of the digestive and endocrine systems are all risk factors for atherosclerosis. In the early stage of atherosclerosis, LDL particles aggregates in the intima of the blood vessel and oxidizes to form oxidized LDL (ox-LDL). Monocytes circulating in the blood bind to chemokines and migrate to
S1P and its receptors
As a sphingomyelin metabolite, S1P plays an important role in cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and other life processes [23]. Sphingomyelin is hydrolyzed by sphingomyelinase into ceramide (Cer), which then is converted by ceramidase to the precursor of S1P, Sphingosine (Sph). S1P is the product of Sph phosphorylation by sphingosine kinases 1 (Sphk1) and sphingosine kinases 2 (Sphk2). S1P in circulation is mainly derived from red blood cells (RBCs),
Anti-inflammatory and promoting vascular neointima formation of S1PR1
Feuerborn et al. [63] proved that raising S1P levels in LDL-R-/- mice exerted anti-atherogenic effects through favorable modulation of endothelial function. Moreover, hematopoietic S1P lyase deficiency mice presented an augment of S1P and suppressed the atherogenic response [64]. In addition, In the context of hypercholesterolemia, using Sphk1 inhibitor to lower endogenous plasma S1P leaded to pro-inflammatory and pro-atherogenic effects [65]. These results all demonstrated an atheroprotective
Improved role of S1PR1 in cardiac remodeling
Ahmed et al. [84] discovered that S1PR1, S1PR2 as well as S1PR3 were distributed in all chambers of the human and rat heart, hinting potential roles of S1PRs on a heart. Compared with the strong expression of S1PR1 and S1PR3 in heart, S1PR2 was in a lower expression, and there was no expression of S1PR4 and S1PR5 in heart. In fact, it was previously reported that the concentration of S1P in plasma was greatly reduced in patients with MI [85]. In a general way, S1PR1 acts as a protector in
Improvement of circulation by S1PR1 in ischemic brain
An in vivo study showed that S1PR1 selective agonists LASW1238 significantly reduced the area of cerebral infarction after the I/R of middle cerebral artery [98]. In a separate study, the researchers found that in mice with laser-induced cortical arteriole thrombosis, the selective S1PR1 modulators RP101075 changed the composition of thrombus via reducing the number of CD45+ cells in the thrombus, and reduced thrombus volume, thus improving post-thrombus microvascular circulation and
Perspective and conclusion
Given the roles in atherosclerosis and ischemia via regulating key segments such as inflammation of ECs, apoptosis and migration of macrophage, neointima formation and angiogenesis, S1PRs may serve as potential targets. For instance, Fingolimod (FTY720), was proved to reduce the size of atherosclerotic lesion in LDL-R−/− mice and Apo E−/− mice fed with a high-cholesterol diet [68]. Moreover, FTY720 has also been confirmed to ameliorate brain injury on ischemic stroke models via improving blood
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (Project 81770490) and the Specialized Research Fund for the Doctoral Program of Higher Education of China (20124324120005).
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2022, Advances in PharmacologyCitation Excerpt :By stimulating its receptors, S1P modulates cell proliferation and migration, angiogenesis, self-immunity and cytokines production. As second messenger operating directly inside the cell, S1P regulates calcium levels, plays a role in DNA synthesis, suppresses apoptosis (Lu, She, Zeng, Yi, & Zhang, 2021) and modulates inflammatory responses, regulating the phosphorylation of IkB and the activation of NF-kB (Alvarez et al., 2010). S1P is also directly associated to specific intracellular targets, like the stimulator of interferon gene (STING) (Anwar & Mehta, 2020) or histone deacetylases (HDACS), therefore influencing the transcription of target genes (Hait et al., 2009).
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