Abstract
Sphingosine 1-phosphate (S1P) is a bioactive lipid that is characterized by a peculiar mechanism of action. In fact, S1P, which is produced inside the cell, can act as an intracellular mediator, whereas after its export outside the cell, it can act as ligand of specific G-protein coupled receptors, which were initially named endothelial differentiation gene (Edg) and eventually renamed sphingosine 1-phosphate receptors (S1PRs). Among the five S1PR subtypes, S1PR1, S1PR2 and S1PR3 isoforms show broad tissue gene expression, while S1PR4 is primarily expressed in immune system cells, and S1PR5 is expressed in the central nervous system. There is accumulating evidence for the important role of S1P as a mediator of many processes, such as angiogenesis, carcinogenesis and immunity, and, ultimately, fibrosis. After a tissue injury, the imbalance between the production of extracellular matrix (ECM) and its degradation, which occurs due to chronic inflammatory conditions, leads to an accumulation of ECM and, consequential, organ dysfunction. In these pathological conditions, many factors have been described to act as pro- and anti-fibrotic agents, including S1P. This bioactive lipid exhibits both pro- and anti-fibrotic effects, depending on its site of action. In this review, after a brief description of sphingolipid metabolism and signaling, we emphasize the involvement of the S1P/S1PR axis and the downstream signaling pathways in the development of fibrosis. The current knowledge of the therapeutic potential of S1PR subtype modulators in the treatment of the cardiac functions and fibrinogenesis are also examined.
Highlights
CARDIAC FIBROSISCardiac fibrosis is a multistep disorder, which arises due to several circumstances, such as inflammation, ischaemia and senescence
Sphingosine 1-phosphate (S1P) is a bioactive lipid that is characterized by a peculiar mechanism of action
S1P, which is produced inside the cell, can act as an intracellular mediator, whereas after its export outside the cell, it can act as ligand of specific G-protein coupled receptors, which were initially named endothelial differentiation gene (Edg) and eventually renamed sphingosine 1-phosphate receptors (S1PRs)
Summary
Cardiac fibrosis is a multistep disorder, which arises due to several circumstances, such as inflammation, ischaemia and senescence. Several miRs have been described as regulators of cardiac fibrosis acting as pro-fibrotic or anti-fibrotic factors on ECM remodeling (black) and on TGFβ /Smad signaling (blue). Recent research has found that epigenetic factors, such as miRs play an important role in tissue remodeling by controlling MMPs and TGF-β/Smad signaling (Figure 1) (Care et al, 2007; Roy et al, 2009; Creemers and van Rooij, 2016; Biglino et al, 2017). The silencing and pharmacological inhibition of SphK1 alters the ratio MMPs/TIMPs, and CTGF expression elicited by RLX indicates that hormone peptides promote an ECM-remodeling phenotype through the activation of endogenous S1P production and SM metabolism (Frati et al, 2015). S1PR2 (Edg5) Most tissues Kd (nM) 16–27 Coupled to: Gαi, Gαq et Gα12/13 S1PR3 (Edg3) Heart Lung Spleen Kidney Intestine Kd (nM) 23–26 Coupled to: Gαi/o, Gαq, and Gα12/13
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