Arginase inhibition augments nitric oxide production and facilitates left ventricular systolic function in doxorubicin-induced cardiomyopathy in mice

Abstract

A metabolizing enzyme arginase can decrease nitric oxide (NO) production by competing with NO synthase for arginine as a substrate, but its pathophysiological role in heart failure remains unknown. We aimed to investigate the effect of pharmacological inhibition of arginase on left ventricular function in doxorubicin‐induced cardiomyopathy in mice. Doxorubicin administration for 5 weeks significantly increased protein expression levels or activity of arginase in the lungs and liver, and caused moderate increase in arginase 2 expression in the aorta. In the lungs, accumulated interstitial cells strongly expressed both arginase 1 and arginase 2 by doxorubicin administration. Echocardiography revealed that administration of a potent, reversible arginase inhibitor N‐omega‐hydroxy‐nor‐l‐arginine completely reversed doxorubicin‐induced decrease in the ejection fraction, in parallel with expression levels of BNP mRNA, without affecting apoptosis, hypertrophy, fibrosis, or macrophage infiltration in the left ventricle. Arginase inhibition reversibly lowered systolic blood pressure, and importantly, it recovered doxorubicin‐induced decline in NO concentration in the serum, lungs, and aorta. Furthermore, arginase inhibition stimulated NO secretion from aortic endothelial cells and peritoneal macrophages in vitro. In conclusion, pharmacological inhibition of arginase augmented NO concentration in the serum, lungs, and aorta, promoted NO‐mediated decrease in afterload for left ventricle, and facilitated left ventricular systolic function in doxorubicin‐induced cardiomyopathy in mice.

Botanical Drug Puerarin Attenuates 6-Hydroxydopamine (6-OHDA)-Induced Neurotoxicity via Upregulating Mitochondrial Enzyme Arginase-2

“…In contrast, arginase-2 (NP_062041) competes with NOSs for the substrate L-arginine [12]. Arginase-2 is recognized as an anti-inflammatory enzyme for its use of arginine toward polyamine synthesis at the expense of NO production [51,52]. In the present study, Western blot analysis verified that puerarin increased the expression of arginase-2 and NM23-H2 in a concentration-dependent manner.…”

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

“…NO is an essential molecular mediator of normally functioning endothelium, and reductions in NO bioavailability lead to DNA damage, lipid peroxidation, cardiomyocyte apoptosis, endothelial cell dysfunction, and reduced cardiac contractility (15,16). L-arginine, a key substrate in NO production, can be alternatively catabolized to urea or converted to N-monomethylarginine (MMA), which results in nitric oxide synthase (NOS) inhibition and less NO bioavailability.…”

Arginase inhibition ameliorates adipose tissue inflammation in mice with diet-induced obesity

“…Arginase is expressed in endothelial and vascular smooth muscle cells and is responsible for converting L-arginine to urea and L-ornithine [33]; thus, arginase competes with iNOS for the substrate L-arginine [14e16], thereby downregulating NO biosynthesis. Therefore, arginase inhibition may increase NO production by shunting L-arginine from the arginase pathway to the endothelial NOS pathway [19,20], which in turn improves endothelial dysfunction [19]. Macrophage infiltration is referred to as a hallmark of inflammation [9], and macrophage infiltration into white adipose tissue (WAT) and secretion of adipokines and cytokines are involved in the initiation of chronic lowgrade inflammatory response observed in obesity [5e9].…”

“…Arginase inhibition may augment NO production by shunting Larginine from the arginase pathway to the endothelial NOS pathway [19,20], thereby improving endothelial dysfunction [19]. Treatment with an arginase inhibitor, N u -hydroxy-nor-L-arginine (nor-HONA), also restored endothelial function in rat adjuvantinduced arthritis [21].…”