on September 29, 2003
Circulation. 2003
Published online before print September 29, 2003, doi: 10.1161/01.CIR.0000092948.04444.C7
Published online before print September 29, 2003, doi: 10.1161/01.CIR.0000092948.04444.C7
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Submitted on December 11, 2002
From the Departments of Anesthesiology and Critical Care Medicine (D.E.B., D.L., S.K., S.B., D.N.), Biomedical Engineering (D.E.B., R.W., A.A.S., J.M.H.), and Medicine (Cardiology Division) (A.C., K.M.M., H.C.C., J.M.H.), Johns Hopkins Medical Institutions, Baltimore, Md. * To whom correspondence should be addressed. E-mail: jhare{at}mail.jhmi.edu.
Background--Although abnormal L-arginine NO signaling contributes to endothelial dysfunction in the aging cardiovascular system, the biochemical mechanisms remain controversial. L-arginine, the NO synthase (NOS) precursor, is also a substrate for arginase. We tested the hypotheses that arginase reciprocally regulates NOS by modulating L-arginine bioavailability and that arginase is upregulated in aging vasculature, contributing to depressed endothelial function. Methods and Results--Inhibition of arginase with (S)-(2-boronoethyl)-L-cysteine, HCl (BEC) produced vasodilation in 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 with the additional arginase inhibitors N-hydroxy-nor-L-arginine (nor-NOHA) and difluoromethylornithine (DFMO). This effect required intact endothelium and was prevented by 1H-oxadiazole quinoxalin-1-one (P<0.05 and P<0.001, respectively), a soluble guanylyl cyclase inhibitor. DFMO-elicited vasodilation was greater in old (O) compared with Y rat aortic rings (60±6% versus 39±6%, P<0.05). In addition, BEC restored depressed L-arginine (10-4 mol/L)-dependent vasorelaxant responses in O rings to those of Y. Arginase activity and expression were increased in O rings, whereas NOS activity and cyclic GMP levels were decreased. BEC and DFMO suppressed arginase activity and restored NOS activity and cyclic GMP levels in O vessels to those of Y. Conclusions--These findings demonstrate that arginase modulates NOS activity, likely by regulating intracellular L-arginine availability. Arginase upregulation contributes to endothelial dysfunction of aging and may therefore be a therapeutic target.
Revised on June 17, 2003
Accepted on June 19, 2003
Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels
Dan E. Berkowitz MD,
Key words: endothelium • aging • nitric oxide • cardiovascular diseases
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