An engineered S1P chaperone attenuates hypertension and ischemic injury

作者：Swendeman Steven L; Xiong Yuquan; Cantalupo Anna; Yuan Hui; Burg Nathalie; Hisano Yu; Cartier Andreane; Liu Catherine H; Engelbrecht Eric; Blaho Victoria; Zhang Yi; Yanagida Keisuke; Galvani Sylvain; Obinata Hideru; Salmon Jane E; Sanchez Teresa; Di Lorenzo Annarita; Hla Timothy

来源：Science Signaling, 2017, 10(492): eaal2722.

DOI：10.1126/scisignal.aal2722

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.

• 出版日期2017-8-15