Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1

Cardiovasc Res. 2017 Nov 1;113(13):1664-1676. doi: 10.1093/cvr/cvx164.

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.

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.

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.

Keywords: Arginase; Diabetes; Fibrosis; Obesity; Vascular dysfunction.

MeSH terms

  • Animals
  • Arginase / antagonists & inhibitors
  • Arginase / genetics
  • Arginase / metabolism*
  • Arginine / blood
  • Blood Glucose / metabolism
  • Blood Pressure
  • Diabetes Mellitus, Experimental / enzymology*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Experimental / prevention & control
  • Diabetes Mellitus, Type 2 / enzymology*
  • 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 / enzymology*
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Enzyme Inhibitors / pharmacology
  • Fibrosis
  • Genetic Predisposition to Disease
  • Insulin / blood
  • Male
  • Metabolic Syndrome / enzymology*
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / physiopathology
  • Metabolic Syndrome / prevention & control
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / metabolism
  • Obesity / drug therapy
  • Obesity / enzymology*
  • Obesity / genetics
  • Obesity / physiopathology
  • Ornithine / blood
  • Oxidative Stress
  • Phenotype
  • Signal Transduction
  • Vascular Diseases / enzymology*
  • Vascular Diseases / genetics
  • Vascular Diseases / physiopathology
  • Vascular Diseases / prevention & control
  • Vascular Stiffness* / drug effects
  • Vasodilation

Substances

  • Blood Glucose
  • Dietary Sucrose
  • Enzyme Inhibitors
  • Insulin
  • Nitric Oxide
  • Arginine
  • Ornithine
  • Arg1 protein, mouse
  • Arginase