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Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension
Abstract
Pulmonary arterial hypertension (PAH), a fatal disease of unknown etiology characterized by impaired regulation of pulmonary hemodynamics and vascular growth, is associated with low levels of pulmonary nitric oxide (NO). Based upon its critical role in mediating vasodilation and cell growth, decrease of NO has been implicated in the pathogenesis of PAH. We evaluated mechanisms for low NO and pulmonary hypertension, including NO synthases (NOS) and factors regulating NOS activity, i.e. the substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls. PAH lungs had normal NOS I–III expression, but substrate arginine levels were inversely related to pulmonary artery pressures. Activity of arginase, an enzyme that regulates NO biosynthesis through effects on arginine, was higher in PAH serum than in controls, with high‐level arginase expression localized by immunostaining to pulmonary endothelial cells. Further, pulmonary artery endothelial cells derived from PAH lung had higher arginase II expression and produced lower NO than control cells in vitro. Thus, substrate availability affects NOS activity and vasodilation, implicating arginase II and alterations in arginine metabolic pathways in the pathophysiology of PAH.
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“NOX4 is the most abundant isoform in ECs, and it is also present in VSMCs and adventitial fibroblasts (10, 265, 736, 832, 876, 1036).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1036]
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Metadata
- Authors
- Xu, W., Kaneko, F. T., Zheng, S., Comhair, S. A. A., Janocha, A. J., Goggans, T., Thunnissen, F. B. J. M., Farver, C., Hazen, S. L., Jennings, C., Dweik, R. A., Arroliga, A. C., & Erzurum, S. C.
- Affiliations
- Cleveland Clinic (US)
- Department of Pathology Canisius Wihelmina Ziekenhuis Nijmegen The Netherlands
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2004-09-13
- Volume
- 18
- Issue
- 14
- Pages
- 1746-1748
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2116905957
- Cited by
- 369
- References
- 75
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 14 · 2023: 10 · 2022: 10 · 2021: 18 · 2020: 12 · 2019: 12 · 2018: 16 · 2017: 23 · 2016: 13 · 2015: 17 · 2014: 21 · 2013: 27 · 2012: 13
- FWCI
- 16.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL 60917, HL 04265, HL076491)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Genetics (clinical) › Vascular Anomalies and Treatments
- Keywords
- pulmonary arterial hypertension, arginase II, nitric oxide production, nitric oxide synthase, arginine metabolism, endothelial cells, pulmonary artery endothelium, vasodilation, pulmonary hypertension pathogenesis, nitric oxide synthase inhibitors
- MeSH terms
- Arginase, Blood Pressure, Cells, Cultured, Endothelium, Vascular, Humans, Hypertension, Pulmonary, Nitric Oxide, Pulmonary Artery
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