Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Cantalupo, A; Sasset, L; Gargiulo, A; Rubinelli, L; Del Gaudio, I; Benvenuto, D; Wadsack, C; Jiang, XC; Bucci, MR; Di Lorenzo, A.
Endothelial Sphingolipid De Novo Synthesis Controls Blood Pressure by Regulating Signal Transduction and NO via Ceramide.
Hypertension. 2020; 75(5):1279-1288 Doi: 10.1161/HYPERTENSIONAHA.119.14507 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

 

Co-authors Med Uni Graz

Del Gaudio Ilaria

Wadsack Christian

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Abstract:

Ceramides are sphingolipids that modulate a variety of cellular processes via 2 major mechanisms: functioning as second messengers and regulating membrane biophysical properties, particularly lipid rafts, important signaling platforms. Altered sphingolipid levels have been implicated in many cardiovascular diseases, including hypertension, atherosclerosis, and diabetes mellitus-related conditions; however, molecular mechanisms by which ceramides impact endothelial functions remain poorly understood. In this regard, we generated mice defective of endothelial sphingolipid de novo biosynthesis by deleting the Sptlc2 (long chain subunit 2 of serine palmitoyltransferase)-the first enzyme of the pathway. Our study demonstrated that endothelial sphingolipid de novo production is necessary to regulate (1) signal transduction in response to NO agonists and, mainly via ceramides, (2) resting eNOS (endothelial NO synthase) phosphorylation, and (3) blood pressure homeostasis. Specifically, our findings suggest a prevailing role of C16:0-Cer in preserving vasodilation induced by tyrosine kinase and GPCRs (G-protein coupled receptors), except for Gq-coupled receptors, while C24:0- and C24:1-Cer control flow-induced vasodilation. Replenishing C16:0-Cer in vitro and in vivo reinstates endothelial cell signaling and vascular tone regulation. This study reveals an important role of locally produced ceramides, particularly C16:0-, C24:0-, and C24:1-Cer in vascular and blood pressure homeostasis, and establishes the endothelium as a key source of plasma ceramides. Clinically, specific plasma ceramides ratios are independent predictors of major cardiovascular events. Our data also suggest that plasma ceramides might be indicative of the diseased state of the endothelium.

Find related publications in this database (using NLM MeSH Indexing)

Acetylcholine - pharmacology

Animals -

Blood Pressure - physiology

Cell Adhesion Molecules - metabolism

Cells, Cultured -

Ceramides - physiology

Endothelial Cells - metabolism

Histamine - pharmacology

Homeostasis -

Male -

Mice -

Mice, Transgenic -

Microfilament Proteins - metabolism

Nitric Oxide - agonists

Nitric Oxide - physiology

Nitric Oxide Synthase Type III - metabolism

Nitroprusside - pharmacology

Phosphoproteins - metabolism

Serine C-Palmitoyltransferase - deficiency

Signal Transduction -

Sphingolipids - biosynthesis

Vascular Endothelial Growth Factor Receptor-2 - physiology

Vasoconstriction - drug effects

Vasoconstriction - physiology

Vasodilation - drug effects

Vasodilation - physiology

Find related publications in this database (Keywords)

blood pressure

ceramides

endothelial

sphingolipids

vascular resistance

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