Dose-Dependent Regulation of NAD(P)H Oxidase Expression by Angiotensin II in Human Endothelial Cells: Protective Effect of Angiotensin II Type 1 Receptor Blockade in Patients With Coronary Artery Disease
Abstract
Objective— Angiotensin II (Ang II)–mediated induction of vascular superoxide anion formation could contribute to the development of endothelial dysfunction, hypertension, and atherosclerosis. An NAD(P)H oxidase has been identified as a major endothelial source of superoxide anions. However, the molecular mechanism underlying the regulation of NAD(P)H oxidase activity in response to Ang II is not well understood. Methods and Results— We investigated the dose-dependent regulation of superoxide anion formation and of NAD(P)H oxidase subunit expression in response to Ang II in human endothelial cells. Ang II regulates superoxide anion formation and the limiting subunit of endothelial NAD(P)H oxidase, gp91-phox, in a dose-dependent manner via Ang II type 1 (AT 1 ) receptor–mediated induction and Ang II type 2 receptor–mediated partial inhibition at higher Ang II concentrations. Furthermore, AT 1 receptor blocker therapy before coronary bypass surgery downregulates the gp91-phox expression in internal mammary artery biopsies of patients with coronary artery disease. Conclusions— Our data support a dose-dependent induction of proatherosclerotic oxidative stress in human endothelial cells in response to Ang II. The expression of NAD(P)H oxidase subunit gp91-phox is critical for endothelial superoxide anion formation. AT 1 receptor blockade has an antiatherosclerotic and antioxidative potential by the reduction of oxidative stress in the vessel wall.
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- Authors
- Rueckschloss, U., Quinn, M. T., Holtz, J., & Morawietz, H.
- Affiliations
- Montana State University (US)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2002-11
- Volume
- 22
- Issue
- 11
- Pages
- 1845-1851
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2149408586
- Cited by
- 216
- References
- 39
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 9 · 2012: 14
- FWCI
- 11.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Novartis Foundation
- Deutsche Forschungsgemeinschaft
- Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung.
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL066575)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- angiotensin II, NADPH oxidase, gp91phox, endothelial dysfunction, angiotensin II type 1 receptor, angiotensin II type 2 receptor, dose-dependent regulation, oxidative stress, atherosclerosis, coronary artery disease, angiotensin receptor blockers, coronary artery bypass grafting, internal mammary artery
- MeSH terms
- NADPH Oxidase 2, Angiotensin II, Coronary Artery Bypass, Benzimidazoles, Biphenyl Compounds, Cells, Cultured, Coronary Artery Disease, Dose-Response Relationship, Drug, Endothelium, Vascular, Humans, Imidazoles, Mammary Arteries, Membrane Glycoproteins, NADH, NADPH Oxidoreductases, Preoperative Care, Pyridines, Receptors, Angiotensin, Renin-Angiotensin System, Retrospective Studies, Superoxides, Tetrazoles, Umbilical Veins, Oxidative Stress, NADPH Oxidases, Receptor, Angiotensin, Type 2, Receptor, Angiotensin, Type 1, Angiotensin Receptor Antagonists
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