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Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.

Abstract：

:Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein-coupled receptor-dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II-induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II-induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis.

journal_name

Nat Med

journal_title

Nature medicine

authors

Cantalupo A,Zhang Y,Kothiya M,Galvani S,Obinata H,Bucci M,Giordano FJ,Jiang XC,Hla T,Di Lorenzo A

doi

10.1038/nm.3934

subject

Has Abstract

pub_date

2015-09-01 00:00:00

pages

1028-1037

issue

9

eissn

1078-8956

issn

1546-170X

journal_volume

21

pub_type

杂志文章

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