An engineered S1P chaperone attenuates hypertension and ischemic injury.

TitleAn engineered S1P chaperone attenuates hypertension and ischemic injury.
Publication TypeJournal Article
Year of Publication2017
AuthorsSwendeman 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
JournalSci Signal
Volume10
Issue492
Date Published2017 Aug 15
ISSN1937-9145
KeywordsAnimals, 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.

DOI10.1126/scisignal.aal2722
Alternate JournalSci Signal
PubMed ID28811382
PubMed Central IDPMC5680089
Grant ListP30 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
Related Faculty: 
Annarita Di Lorenzo, Ph.D. Teresa Sanchez, Ph.D.

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