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Journal article
Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats
Journal of applied physiology (1985), v 107(4), pp 1249-1257
01 Oct 2009
PMID: 19661445
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O
2
−
) production than young. Acute inhibition of both NOS, with
N
G
-nitro-
l
-arginine methyl ester, and arginase, with 2(
S
)-amino- 6-boronohexanoic acid (ABH), significantly reduced O
2
−
production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore,
S
-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al.,
Circ Res
101: 692–702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O
2
−
production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent
S
-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.
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Details
- Title
- Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats
- Creators
- Jae Hyung Kim - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MarylandLukasz J. Bugaj - Johns Hopkins UniversityYoung Jun OhTrinity J. Bivalacqua - Johns Hopkins UniversitySungwoo Ryoo - Kangwon National UniversityKevin G. Soucy - Johns Hopkins UniversityLakshmi Santhanam - Johns Hopkins UniversityAlanah Webb - Johns Hopkins UniversityAndre Camara - Johns Hopkins UniversityGautam Sikka - Johns Hopkins UniversityDaniel Nyhan - Johns Hopkins UniversityArtin A. Shoukas - Johns Hopkins UniversityMonica Ilies - University of PennsylvaniaDavid W. Christianson - University of PennsylvaniaHunter C. Champion - University of PittsburghDan E. Berkowitz - Johns Hopkins University
- Publication Details
- Journal of applied physiology (1985), v 107(4), pp 1249-1257
- Publisher
- American Physiological Society
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000270854000031
- Scopus ID
- 2-s2.0-70350117109
- Other Identifier
- 991020545117204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Physiology
- Sport Sciences