title: 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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Toya
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Daihiko
authors.initials: D
authors.lastname: Hakuno
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Yasunaga
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kujiraoka
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
keywords: Endothelial cell; heart failure; macrophage; nitric oxide