Research ArticlePharmacology

An engineered S1P chaperone attenuates hypertension and ischemic injury

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Science Signaling  15 Aug 2017:
Vol. 10, Issue 492, eaal2722
DOI: 10.1126/scisignal.aal2722

Targeting S1P1 on endothelial cells

The lipid mediator sphingosine 1-phosphate (S1P) is ferried in the blood by different chaperone proteins, the identity of which determines the specific signaling pathway triggered by S1P binding to its receptor S1P1. When bound to the lipoprotein ApoM+HDL, S1P suppresses endothelial cell inflammation and atherosclerosis. However, globally increasing HDL abundance does not confer these benefits, and ApoM is unstable when not bound to HDL. Swendeman et al. generated a stable form of ApoM (ApoM-Fc) that bound to S1P and activated S1P1 receptors in a sustained manner in endothelial cells. ApoM-Fc–S1P treatment of mice reduced hypertension induced by angiotensin II and improved outcomes after experimentally induced myocardial infarction or stroke, without inducing the lymphopenia characteristic of S1P1 agonists. These results provide proof-of-concept evidence that developing a chaperone that targets S1P to S1P1 selectively on endothelial cells could be used to treat cardiovascular diseases.


Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M–containing HDL (ApoM+HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein–coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases. We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc could be a viable therapeutic strategy in vascular diseases.

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