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Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2017 Nov 01; Vol. 113 (13), pp. 1664-1676. - Publication Year :
- 2017
-
Abstract
- Aims: Elevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology.<br />Methods and Results: To test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment.<br />Conclusion: Vascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Arginase antagonists & inhibitors
Arginase genetics
Arginine blood
Blood Glucose metabolism
Blood Pressure
Diabetes Mellitus, Experimental genetics
Diabetes Mellitus, Experimental physiopathology
Diabetes Mellitus, Experimental prevention & control
Diabetes Mellitus, Type 2 genetics
Diabetes Mellitus, Type 2 physiopathology
Diabetes Mellitus, Type 2 prevention & control
Diet, High-Fat
Dietary Sucrose
Endothelium, Vascular drug effects
Endothelium, Vascular pathology
Endothelium, Vascular physiopathology
Enzyme Inhibitors pharmacology
Fibrosis
Genetic Predisposition to Disease
Insulin blood
Male
Metabolic Syndrome genetics
Metabolic Syndrome physiopathology
Metabolic Syndrome prevention & control
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide metabolism
Obesity drug therapy
Obesity genetics
Obesity physiopathology
Ornithine blood
Oxidative Stress
Phenotype
Signal Transduction
Vascular Diseases genetics
Vascular Diseases physiopathology
Vascular Diseases prevention & control
Vasodilation
Arginase metabolism
Diabetes Mellitus, Experimental enzymology
Diabetes Mellitus, Type 2 enzymology
Endothelium, Vascular enzymology
Metabolic Syndrome enzymology
Obesity enzymology
Vascular Diseases enzymology
Vascular Stiffness drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 113
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 29048462
- Full Text :
- https://doi.org/10.1093/cvr/cvx164