Arginase: a critical regulator of nitric oxide synthesis and vascular function

Abstract

1. Arginase is the focal enzyme of the urea cycle hydrolysing L-arginine to urea and L-ornithine. Emerging studies have identified arginase in the vasculature and have implicated this enzyme in the regulation of nitric oxide (NO) synthesis and the development of vascular disease. 2. Arginase inhibits the production of NO via several potential mechanisms, including competition with NO synthase (NOS) for the substrate L-arginine, uncoupling of NOS resulting in the generation of the NO scavenger, superoxide and peroxynitrite, repression of the translation and stability of inducible NOS protein, inhibition of inducible NOS activity via the generation of urea and by sensitization of NOS to its endogenous inhibitor asymmetric dimethyl-L-arginine. 3. Upregulation of arginase inhibits endothelial NOS-mediated NO synthesis and may contribute to endothelial dysfunction in hypertension, ageing, ischaemia-reperfusion and diabetes. 4. Arginase also redirects the metabolism of L-arginine to L-ornithine and the formation of polyamines and L-proline, which are essential for smooth muscle cell growth and collagen synthesis. Therefore, the induction of arginase may also promote aberrant vessel wall remodelling and neointima formation. 5. Arginase represents a promising novel therapeutic target that may reverse endothelial and smooth muscle cell dysfunction and prevent vascular disease.

Figure 1

Metabolism of L-arginine by nitric oxide synthase (NOS) and arginase. NOS oxidatively degrades L-arginine into L-citrulline and nitric oxide (NO) while arginase hydrolyzes L-arginine to urea and L-ornithine.

Figure 2

Model for the induction of vascular disease by arginase. In the circulation, the generation of NO by eNOS in endothelial cells (EC) plays a fundamental role in maintaining vascular homeostasis by inhibiting vascular tone, platelet aggregation, and inflammation. In addition, the iNOS-mediated formation of NO by vascular smooth muscle cells (SMC) functions in a negative feedback manner to inhibit collagen synthesis and SMC growth, and stimulate SMC apoptosis. However, arginase may promote both EC and SMC dysfunction by modulating the metabolism of L-arginine. In particular, the ability of arginase to compete with eNOS for the substrate L-arginine impairs NO synthesis and leads to endothelial dysfunction. In addition, arginase redirects the metabolism of L-arginine from NO to L-ornithine and the formation of polyamines and L-proline by the action of ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT), respectively. The formation of polyamines and L-proline play an essential role in SMC proliferation and collagen deposition promoting the development of vascular lesions. These actions of arginase are further amplified by the repression of NO release, which serves as a well-established inhibitor of SMC growth and collagen synthesis.