Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure
| Autor: | Frank J. Giordano, Hideru Obinata, Timothy Hla, Sylvain Galvani, Yi Zhang, Annarita Di Lorenzo, Milankumar Kothiya, Xian-Cheng Jiang, Mariarosaria Bucci, Anna Cantalupo |
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| Přispěvatelé: | Cantalupo, A, Zhang, Ying, Kothiya, M, Galvani, S, Obinata, H, Bucci, M, Giordano, Fj, Jiang, Xc, Solin, HEIKKI LAURI ABEL, Di Lorenzo, A |
| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Nitric Oxide Synthase Type III Endothelium Nogo Proteins Blood Pressure Biology General Biochemistry Genetics and Molecular Biology Mice chemistry.chemical_compound Sphingosine Myriocin Internal medicine Chlorocebus aethiops medicine Animals Homeostasis Humans Endothelial dysfunction endothelium dysfunction lipid mediators blood pressure Autocrine signalling Sphingolipids Serine C-palmitoyltransferase General Medicine Lipid signaling medicine.disease Sphingolipid Cell biology Receptors Lysosphingolipid HEK293 Cells Endocrinology medicine.anatomical_structure chemistry COS Cells Endothelium Vascular Lysophospholipids Myelin Proteins |
| Zdroj: | Nature Medicine. 21:1028-1037 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.3934 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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