Title | An engineered S1P chaperone attenuates hypertension and ischemic injury. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Swendeman, SL, Xiong, Y, Cantalupo, A, Yuan, H, Burg, N, Hisano, Y, Cartier, A, Liu, CH, Engelbrecht, E, Blaho, V, Zhang, Y, Yanagida, K, Galvani, S, Obinata, H, Salmon, JE, Sanchez, T, Di Lorenzo, A, Hla, T |
Journal | Sci Signal |
Volume | 10 |
Issue | 492 |
Date Published | 2017 Aug 15 |
ISSN | 1937-9145 |
Keywords | Animals, Apolipoproteins M, Endothelium, Vascular, Human Umbilical Vein Endothelial Cells, Humans, Hypertension, Lipoproteins, HDL, Lysophospholipids, Male, Mice, Mice, Knockout, Protein Binding, Receptors, Fc, Receptors, Lysosphingolipid, Reperfusion Injury, Signal Transduction, Sphingosine |
Abstract | 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 (ApoMHDL), 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. |
DOI | 10.1126/scisignal.aal2722 |
Alternate Journal | Sci Signal |
PubMed ID | 28811382 |
PubMed Central ID | PMC5680089 |
Grant List | P30 CA016087 / CA / NCI NIH HHS / United States U54 HL117798 / HL / NHLBI NIH HHS / United States R01 HL126913 / HL / NHLBI NIH HHS / United States R01 HL094465 / HL / NHLBI NIH HHS / United States R37 HL067330 / HL / NHLBI NIH HHS / United States R15 HL089933 / HL / NHLBI NIH HHS / United States R01 HL067330 / HL / NHLBI NIH HHS / United States UL1 TR002384 / TR / NCATS NIH HHS / United States R01 HL089934 / HL / NHLBI NIH HHS / United States R35 HL135821 / HL / NHLBI NIH HHS / United States |