期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 40, 期 1, 页码 145-158出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/atv.0000615456.97862.30
关键词
angiotensin II; glucagon-like peptide-1 receptor; hypertension; inflammation; liraglutide; oxidative stress
资金
- German Research Foundation [DFG STE2528/2-1]
- Center of Thrombosis and Hemostasis (Mainz, Germany) - Federal Ministry of Education and Research [BMBF 01EO1003]
- TransMed PhD Program at the University Medical Center Mainz
- vascular biology research grant within the collaborative research group Novel and neglected cardiovascular risk factors from the Boehringer Ingelheim Foundation
- DFG [WE4361/7-1]
- BMBF [01EO1003]
- CIHR (Canadian Institutes of Health Research) [154321]
- BBDC (Banting & Best Diabetes Centre)-Novo Nordisk Chair in Incretin Biology
- Novo Nordisk, Inc.
- FNP (Foundation for Polish Science) Team Tech-Core Facility program
Objective: Cardiovascular outcome trials demonstrated that GLP-1 (glucagon-like peptide-1) analogs including liraglutide reduce the risk of cardiovascular events in type 2 diabetes mellitus. Whether GLP-1 analogs reduce the risk for atherosclerosis independent of glycemic control is challenging to elucidate as the GLP-1R (GLP-1 receptor) is expressed on different cell types, including endothelial and immune cells. Approach and Results: Here, we reveal the cardio- and vasoprotective mechanism of the GLP-1 analog liraglutide at the cellular level in a murine, nondiabetic model of arterial hypertension. Wild-type (C57BL/6J), global (Glp1r(-/-)), as well as endothelial (Glp1r(f)lox/floxxCdh5(cre)) and myeloid cell-specific knockout mice (Glp1r(flox/flox)xLysM(cre)) of the GLP-1R were studied, and arterial hypertension was induced by angiotensin II. Liraglutide treatment normalized blood pressure, cardiac hypertrophy, vascular fibrosis, endothelial dysfunction, oxidative stress, and vascular inflammation in a GLP-1R-dependent manner. Mechanistically, liraglutide reduced leukocyte rolling on the endothelium and infiltration of myeloid Ly6G(-)Ly6C(+) and Ly6G(+)Ly6C(+) cells into the vascular wall. As a consequence, liraglutide prevented vascular oxidative stress, reduced S-glutathionylation as a marker of eNOS (endothelial NO synthase) uncoupling, and increased NO bioavailability. Importantly, all of these beneficial cardiovascular effects of liraglutide persisted in myeloid cell GLP-1R-deficient (Glp1r(flox/flox)xLysM(cre)) mice but were abolished in global (Glp1r(-/-)) and endothelial cell-specific (Glp1r(flox/flox)xCdh5(cre)) GLP-1R knockout mice. Conclusions: GLP-1R activation attenuates cardiovascular complications of arterial hypertension by reduction of vascular inflammation through selective actions requiring the endothelial but not the myeloid cell GLP-1R.
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