Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels
Abstract
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.
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Exacerbated arginase activity can decrease l-arginine levels and cause eNOS uncoupling.
“Exacerbated arginase activity can decrease l-arginine levels and cause eNOS uncoupling (91, 144, 667, 804, 1039).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [91]
Citrulline is an allosteric inhibitor of arginase enzyme, preventing the endothelial enzymic breakdown of arginine, the substrate for NOS, and raising the local arginine concentration.
“citrulline is an allosteric inhibitor of arginase enzyme, hence preventing the endothelial enzymic breakdown of arginine, the substrate for NOS, and raising the local arginine concentration (Berkowitz et al. 2006; Bailey et al. 2015)”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Berkowitz et al. 2006
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- Authors
- Berkowitz, D. E., White, R., Li, D., Minhas, K. M., Cernetich, A., Kim, S., Burke, S., Shoukas, A. A., Nyhan, D., Champion, H. C., & Hare, J. M.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Circulation
- Published
- 2003-10-21
- Volume
- 108
- Issue
- 16
- Pages
- 2000-2006
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2120046557
- Cited by
- 486
- References
- 34
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 11 · 2023: 14 · 2022: 17 · 2021: 23 · 2020: 26 · 2019: 20 · 2018: 21 · 2017: 19 · 2016: 13 · 2015: 24 · 2014: 25 · 2013: 32 · 2012: 36
- FWCI
- 9.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag021523-05)
- National Institute on Aging (R01 AG-021523)
- National Heart, Lung, and Blood Institute (R01 HL65455, R01HL065455)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- arginase, nitric oxide synthase, endothelial dysfunction, nitric oxide signaling, vasodilation, soluble guanylate cyclase, cyclic GMP, aorta, arginase inhibition, difluoromethylornithine, nor-NOHA
- MeSH terms
- Soluble Guanylyl Cyclase, Aging, Animals, Arginase, Arginine, Blood Vessels, Disease Models, Animal, Endothelium, Vascular, Enzyme Inhibitors, Cyclic GMP, Guanylate Cyclase, Vasodilation, Vasodilator Agents, Rats, Wistar, Receptors, Cytoplasmic and Nuclear, Nitric Oxide Synthase, Rats, In Vitro Techniques
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