Arginase Activities and Global Arginine Bioavailability in Wild-Type and ApoE-Deficient Mice: Responses to High Fat and High Cholesterol Diets

Sidney M Morris,Tracy Hulderman,Petia P Simeonova,Rebecca Chapman,Michael Kashon,Rebecca Salmen-Muniz,Aaron Erdely,Diane Kepka-Lenhart

doi:10.1371/journal.pone.0015253

Sidney M Morris, Tracy Hulderman + Show 6 more

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https://doi.org/10.1371/journal.pone.0015253

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Abstract

Increased catabolism of arginine by arginase is increasingly viewed as an important pathophysiological factor in cardiovascular disease, including atherosclerosis induced by high cholesterol diets. Whereas previous studies have focused primarily on effects of high cholesterol diets on arginase expression and arginine metabolism in specific blood vessels, there is no information regarding the impact of lipid diets on arginase activity or arginine bioavailability at a systemic level. We, therefore, evaluated the effects of high fat (HF) and high fat-high cholesterol (HC) diets on arginase activity in plasma and tissues and on global arginine bioavailability (defined as the ratio of plasma arginine to ornithine + citrulline) in apoE−/− and wild-type C57BL/6J mice. HC and HF diets led to reduced global arginine bioavailability in both strains. The HC diet resulted in significantly elevated plasma arginase in both strains, but the HF diet increased plasma arginase only in apoE−/− mice. Elevated plasma arginase activity correlated closely with increased alanine aminotransferase levels, indicating that liver damage was primarily responsible for elevated plasma arginase. The HC diet, which promotes atherogenesis, also resulted in increased arginase activity and expression of the type II isozyme of arginase in multiple tissues of apoE−/− mice only. These results raise the possibility that systemic changes in arginase activity and global arginine bioavailability may be contributing factors in the initiation and/or progression of cardiovascular disease.

Highlights

Arginine metabolism plays important roles in vascular function in health and disease
The key enzymes involved in arginine metabolism in the vasculature are the nitric oxide synthases and the arginases, both of which use arginine as a substrate [1], and dysregulated activity or expression of these enzymes has been linked to multiple types of endothelial dysfunction and cardiovascular disease [2,3,4,5]
Because the high cholesterol (HC) diet differed from the standard chow diet with regard to both fat and cholesterol content, the high fat (HF) diet was included to differentiate any effects of increased fat content alone

Summary

Introduction

Arginine metabolism plays important roles in vascular function in health and disease. The key enzymes involved in arginine metabolism in the vasculature are the nitric oxide synthases and the arginases, both of which use arginine as a substrate [1], and dysregulated activity or expression of these enzymes has been linked to multiple types of endothelial dysfunction and cardiovascular disease [2,3,4,5]. In models of endothelial dysfunction as a consequence of aging, ischemiareperfusion or hypertension, vascular arginase has been shown to be elevated [10,11,12,13,14,15,16] Both arginase inhibition and arginine supplementation restore vascular function and nitric oxide production, indicating a role of substrate limitation by arginase for endothelial nitric oxide synthase [10,11,12,13,15,16]. The effects of diets with varying lipid and cholesterol content on systemic arginase activity and global arginine bioavailability have not been evaluated

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