Selective Endothelial Overexpression of Arginase II Induces Endothelial Dysfunction and Hypertension and Enhances Atherosclerosis in Mice

Boris L Vaisman,Alan T Remaley,Sidney M Morris,Xiao L Moore,Yi Fu,Jaye P F Chin-Dusting,Karen L Andrews,Katherine C Wood,Diane M Kepka-Lenhart,Sacha M L Khong

doi:10.1371/journal.pone.0039487

Abstract

BackgroundCardiovascular disorders associated with endothelial dysfunction, such as atherosclerosis, have decreased nitric oxide (NO) bioavailability. Arginase in the vasculature can compete with eNOS for L-arginine and has been implicated in atherosclerosis. The aim of this study was to evaluate the effect of endothelial-specific elevation of arginase II expression on endothelial function and the development of atherosclerosis.Methodology/Principal FindingsTransgenic mice on a C57BL/6 background with endothelial-specific overexpression of human arginase II (hArgII) gene under the control of the Tie2 promoter were produced. The hArgII mice had elevated tissue arginase activity except in liver and in resident peritoneal macrophages, confirming endothelial specificity of the transgene. Using small-vessel myography, aorta from these mice exhibited endothelial dysfunction when compared to their non-transgenic littermate controls. The blood pressure of the hArgII mice was 17% higher than their littermate controls and, when crossed with apoE −/− mice, hArgII mice had increased aortic atherosclerotic lesions.ConclusionWe conclude that overexpression of arginase II in the endothelium is detrimental to the cardiovascular system.

Highlights

Arginase, a critical hepatic enzyme in the urea cycle, catalyses the conversion of L-arginine to urea and ornithine
We conclude that overexpression of arginase II in the endothelium is detrimental to the cardiovascular system
Studies examining the effect of high fat and high cholesterol diets on systemic L-arginine bioavailability and arginase activity suggest that arginase may contribute to the initiation of atherosclerosis [13]

Summary

Introduction

A critical hepatic enzyme in the urea cycle, catalyses the conversion of L-arginine to urea and ornithine. It exists in two isoforms: arginase I in the cytoplasm and arginase II in the mitochondria. Vascular arginase is thought to compete with endothelial nitric oxide synthase (eNOS) for L-arginine. Upregulation of arginase activity and expression has been reported to play a role in various vascular pathologies, such as pulmonary hypertension associated with sickle cell disease [1], primary pulmonary arterial hypertension, [2] ischemia-reperfusion, [3] uremia, [4] as well as various animal models of arterial hypertension, [5] aging, [6] sexual arousal, [7,8] diabetes [9] and atherosclerosis [10,11,12]. The aim of this study was to evaluate the effect of endothelial-specific elevation of arginase II expression on endothelial function and the development of atherosclerosis

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Conclusion