Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels

• DOI: 10.1161/01.cir.0000092948.04444.c7
• Publication Date: 2003-09-30T01:05:13Z
• Authors: Dan E. Berkowitz; Ron White; Dechun Li; Khalid M. Minhas; Amy Cernetich; Soonyul Kim; Sean Burke; Artin A. Shoukas; Daniel Nyhan; Hunter C. Champion; Joshua M. Hare
• Keywords: Endothelial Dysfunction

Background— Although abnormal l -arginine NO signaling contributes to endothelial dysfunction in the aging cardiovascular system, biochemical mechanisms remain controversial. -arginine, synthase (NOS) precursor, is also a substrate for arginase. We tested hypotheses that arginase reciprocally regulates NOS by modulating bioavailability and upregulated vasculature, contributing depressed function. Methods Results— Inhibition of with (S)-(2-boronoethyl)- -cysteine, HCl (BEC) produced vasodilation aortic rings from young (Y) adult rats (maximum effect, 46.4±9.4% at 10 −5 mol/L, P <0.01). Similar vasorelaxation was elicited additional inhibitors N -hydroxy-nor- (nor-NOHA) difluoromethylornithine (DFMO). This effect required intact endothelium prevented 1H-oxadiazole quinoxalin-1-one ( <0.05 <0.001, respectively), soluble guanylyl cyclase inhibitor. DFMO-elicited greater old (O) compared Y rat (60±6% versus 39±6%, <0.05). In addition, BEC restored (10 −4 mol/L)–dependent vasorelaxant responses O those Y. Arginase activity expression were increased rings, whereas cyclic GMP levels decreased. DFMO suppressed vessels Conclusions— These findings demonstrate modulates activity, likely regulating intracellular availability. upregulation may therefore be therapeutic target.