Can another lipid, sphingosine-1-phosphate, treat atherosclerosis?

This editorial refers to ‘Sphingosine-1-phosphate receptor 3 regulates the transendothelial transport of high-density lipoproteins and low-density lipoproteins in opposite ways’, by S. Velagapudi et al., https://doi.org/10.1093/cvr/cvad183.

Reviews of atherosclerosis written more than 50 years ago describe the disease as due to the accumulation of cholesterol-rich lipoproteins within the arterial wall followed by inflammation and a white cell response.¹ For this reason, reduction of circulating LDL levels is the most effective approach to prevention and regression of atherosclerosis lesions. Another approach to this disease, the reduction of the secondary effects of lipid deposition, i.e. the inflammatory status of white blood cells, has also been touted as a means to prevent cardiovascular events.² With the increased knowledge of white blood cells, understanding changes in the biology of vascular macrophages and other cells has captivated the attention of cardiovascular researchers and become the primary focus of many recent reviews of this disease.^3,4

A number of investigators, including some authors of this paper, have uncovered the receptors responsible for movement of lipoproteins into and across the endothelial cell barrier. Scavenger receptor-BI (SCARB1, SR-BI)⁵ and activin-like kinase 1 (ACVLR1, ALK1)⁶ mediate endothelial cell LDL transcytosis and their deletion reduced atherosclerosis. For SR-BI, the story is more complicated, as endothelial cell SR-BI overexpression also reduces atherosclerosis,⁷ presumably because it improves the actions of HDL. It is very curious that endothelial overexpression and knockout both reduce atherosclerosis.

Sphingosine-1-phosphate (S1P), a component of HDL, binding to its endothelial cell receptor sphingosine-1-phosphate receptor 3 (S1P3) improves endothelial function and reduces atherosclerosis.⁸ Could S1P also mediate endothelial lipid transport, vascular inflammation, and atherosclerosis? Velagapudi et al.⁹ show that endothelial cell transcytosis and anti-inflammatory processes are linked; both are regulated by S1P. They overexpressed S1P3 specifically in endothelial cells. This led to changes in circulating lipids and also atherosclerosis. To show this, the investigators created apoE-deficient mice with endothelial cell specific knockin of S1P3 (S1P3-iECKI) and compared them to apoE-deficient mice (control). Plasma levels of cholesterol and triglyceride did not initially differ between S1P3-iECKI mice and control mice with chow diet but after 30 weeks of Western diet, S1P3-iECKI mice had higher levels of HDL and lower non-HDL cholesterol. S1P3-iECKI also had reduced atherosclerosis (60% less fatty lesions) than control mice. Thus, overexpression of SiP3 was protective, but this protection might have been due to changes in circulating lipoproteins. The reasons for these changes in lipoproteins due to S1P3 overexpression only in endothelial cells were not explained.

Increased endothelial expression of S1P3 altered transendothelial transport of lipoproteins. HDL transcytosis was increased. In contrast, SR-BI transcytosis of LDL was reduced by S1P/S1P3 interaction. This was shown by assessing transport of HDL, LDL, and Evans blue dye from blood into the peritoneal cavity of Lipopolysaccharide-treated mice.

They then went on to dissect the changes in endothelial cell biology that led to reduced atherosclerosis. In vitro stimulation with an S1P3 agonist CYM5541 increased the transport of ¹²⁵I-HDL but decreased the transport of ¹²⁵I-LDL through human aortic endothelial cells. Conversely, knockdown of S1P3 or the S1P3 inhibitor TY52156 decreased the transport of ¹²⁵I-HDL but increased the transport of ¹²⁵I-LDL, indicating that S1P3 regulates transport of HDL and LDL but in opposite directions. These changes in transcytosis were paralleled by changes in cellular binding of HDL and LDL.

Which lipoprotein transcytosis receptors were altered in this experiment? Cell surface biotinylation experiments showed that the activation of the S1P3 receptor increases the cell surface abundance of SR-BI. Activation of S1P3 failed to stimulate the transport of ¹²⁵I-HDL through endothelial cells when SR-BI was silenced. Transendothelial transport of LDL was limited by the abundance of SR-BI and ALK1 but not by LDL receptor (LDLR). By performing knockdown experiments, the authors showed that either there is a co-ordination between these receptors or that the knockdown siRNAs had some degree of cross reactivity. LDLRs were increased with ACVLR1 or SCARB1 knockdown. Knockdown of SCARB1 or LDLR also reduced ALK1 protein expression.

These studies lead to the intriguing possibility that a new approach to preventing or treating atherosclerosis could be via activation of the S1P/S1P3 pathway. Molecules to modulate this pathway are available. This would affect disease via a mechanism that is exclusive of changing circulating lipid levels or inflammatory cells. While tantalizing, this idea needs much more experimental data. Other studies will need to determine the following: 1) why the S1P3 overexpression changes circulating lipoproteins levels, 2) whetherthe reductions of atherosclerosis are seen with other models, e.g. LDLR knockout, 3) whether the pathological improvements are exclusive of thelipoprotein alterations, and finally, 4) whether long-term induction of S1P3 or infusion of activating ligands have some unimagined untowardeffects. So, a lot to learn.

References

Author notes