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Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vesselsBACKGROUND: 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.
Document ID
20040087507
Acquisition Source
Legacy CDMS
Document Type
Reprint (Version printed in journal)
Authors
Berkowitz, Dan E.
(Johns Hopkins Medical Institutions Baltimore, Md, United States)
White, Ron
Li, Dechun
Minhas, Khalid M.
Cernetich, Amy
Kim, Soonyul
Burke, Sean
Shoukas, Artin A.
Nyhan, Daniel
Champion, Hunter C.
Hare, Joshua M.
Date Acquired
August 21, 2013
Publication Date
October 21, 2003
Publication Information
Publication: Circulation
Volume: 108
Issue: 16
ISSN: 0009-7322
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: R01AG021523
CONTRACT_GRANT: R01HL-65455
Distribution Limits
Public
Copyright
Other
Keywords
Non-NASA Center
NASA Program Biomedical Research and Countermeasures
NASA Discipline Cardiopulmonary

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