Abstract 13526: Arginase Inhibition Improves Left Ventricular Systolic Dysfunction in Murine Doxorubicin-Induced Heart Failure, and Increased Arginase Activity Correlates With Cardiac Dysfunction in Patients With Systolic Heart Failure
Introduction: Imbalance between nitric oxide (NO) and reactive oxygen species (ROS) is important in cardiovascular pathophysiology. An arginine-metabolizing enzyme arginase regulates NO production by competing with NO synthase for a substrate arginine. We investigated its role in murine doxorubicin (Dox)-induced heart failure (HF) and in patients with systolic HF.
Methods: PBS, Dox (5 mg/kg/week), or Dox plus an arginase inhibitor nor-NOHA (40 mg/day) was administered i.p. to adult male C57BL/6 mice for five weeks. Expression and activity of tissue arginase, echocardiography, LV remodeling, and NO concentration were analyzed at eight weeks. NO secretion from cultured cells was examined. In human study, 35 patients each of chronic systolic HF (LV ejection fraction (EF), 31.3 ± 10.4%) and control subjects were registered. We examined echocardiography, pulse wave velocity (PWV), blood concentration of arginine, ornithine, NO, and hydroperoxide, and performed univariate and stepwise multivariate analyses.
Results: (1) Dox administration to mice increased expression levels of arginase 1 and 2 in the lung and activity in the lung and liver. (2) Echocardiography revealed that nor-NOHA completely reversed Dox-induced decrease in the EF (n = 10 each), in parallel with expression levels of BNP mRNA, without affecting LV remodeling. (3) nor-NOHA reversibly lowered systolic blood pressure up to 12.1%. (4) nor-NOHA significantly improved Dox-induced decline in NO concentration in the serum, lung, and aorta, and stimulated NO secretion from aortic endothelial cells and peritoneal macrophages in vitro. (5) Plasma ornithine/arginine (O/A) ratio, indicating systemic arginase activity, significantly increased in patients with systolic HF compared with controls. Interestingly, O/A ratio strongly correlated with the inferior vena cava diameter, PWV, and decline in serum NO concentration and NO/ROS ratio, and a trend was revealed in correlation with BNP level.
Conclusions: Arginase inhibition improves LV systolic dysfunction in murine Dox-induced HF, and increased arginase activity correlates with preload and afterload of the LV in patients with systolic HF, highlighting the pathophysiological role of arginase on vascular complications in the disease.
- © 2013 by American Heart Association, Inc.