Arginase: The Emerging Therapeutic Target for Vascular Oxidative Stress and Inflammation

Abstract

Oxidative stress and inflammation in the vascular wall are essential mechanisms of atherosclerosis and vascular dysfunctions associated with risk factors such as metabolic diseases, aging, hypertension, etc. Evidence has been provided that activation of the vascular endothelial cells in the presence of the risk factors promotes oxidative stress and vascular inflammatory responses, leading to acceleration of atherosclerotic vascular disease. Increasing number of studies from recent years demonstrates that uncoupling of endothelial nitric oxide synthase (eNOS), whereby the enzyme eNOS produces detrimental amount of superoxide anion O2MathClass-bin− instead the vasoprotective nitric oxide (NO⋅), plays a critical role in vascular dysfunction under various pathophysiological conditions and in aging. The mechanisms of eNOS-uncoupling seem multiple and complex. Recent research provides emerging evidence supporting an essential role of increased activity of arginases including arginase-I and arginase-II in causing eNOS-uncoupling, which results in vascular oxidative stress and inflammatory responses, and ultimately leading to vascular diseases. This review article will summarize the most recent findings on the functional roles of arginases in vascular diseases and/or dysfunctions and the underlying mechanisms in relation to oxidative stress and inflammations. Moreover, regulatory mechanisms of arginases in the vasculature are reviewed and the future perspectives of targeting arginases as therapeutic options in vascular diseases are discussed.

p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

“…The endothelial cells express both Arg-I and Arg-II and share similar functions with respect to the negative regulation of eNOS functions [9]. Compelling evidence implicates that Arg-II plays a dominant role in eNOSuncoupling in human and mouse blood vessels [10,11].…”

“…The mechanisms of eNOS-uncoupling are multifactorial and have not been fully elucidated [7]. Recent studies including our own demonstrate that the L-arginine ureahydrolase, arginase, including type-I and type-II arginase (Arg-I and Arg-II), is involved in eNOS-uncoupling in vascular diseases [8][9][10].…”

K Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

“…In addition, arginases promote endothelial NO synthase (eNOS) uncoupling through enzymatic competition with the substrate l ‐arginine, thereby generating ROS (Yang & Ming, 2013). An increase in ROS generation causes endothelial dysfunction via the functional inactivation of NO.…”

Arginase inhibition attenuates arteriogenesis and interferes with M2 macrophage accumulation

“…Indeed it has been previously been described that exogenously added L-arginine can be channeled to NO production by endothelial NOS3 in vitro. 22 Interestingly, L-arginine supplementation resulted in decreased nitrate/ nitrite levels in supernatants of SMCs. Recent studies have shown that the neuronal isoform of NOS, NOS1, is almost not present in arteriolar ECs, but is strongly expressed in collateral arteriolar SMCs.…”