Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 5 (Nox5) Regulation by Angiotensin II and Endothelin-1 Is Mediated via Calcium/Calmodulin-Dependent, Rac-1-Independent Pathways in Human Endothelial Cells
Open accessAbstract
Rationale : Although Nox5 (Nox2 homolog) has been identified in the vasculature, its regulation and functional significance remain unclear. Objectives : We sought to test whether vasoactive agents regulate Nox5 through Ca 2+ /calmodulin-dependent processes and whether Ca 2+ -sensitive Nox5, associated with Rac-1, generates superoxide (O 2 ·− ) and activates growth and inflammatory responses via mitogen-activated protein kinases in human endothelial cells (ECs). Methods and Results : Cultured ECs, exposed to angiotensin II (Ang II) and endothelin (ET)-1 in the absence and presence of diltiazem (Ca 2+ channel blocker), calmidazolium (calmodulin inhibitor), and EHT1864 (Rac-1 inhibitor), were studied. Nox5 was downregulated with small interfering RNA. Ang II and ET-1 increased Nox5 expression (mRNA and protein). Effects were inhibited by actinomycin D and cycloheximide and blunted by diltiazem, calmidazolium and low extracellular Ca 2+ ([Ca 2+ ] e ). Ang II and ET-1 activated NADPH oxidase, an effect blocked by low [Ca 2+ ] e , but not by EHT1864. Nox5 knockdown abrogated agonist-stimulated O 2 ·− production and inhibited phosphorylation of extracellular signal-regulated kinase (ERK)1/2, but not p38 MAPK (mitogen-activated protein kinase) or SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase). Nox5 small interfering RNA blunted Ang II-induced, but not ET-1-induced, upregulation of proliferating-cell nuclear antigen and vascular cell adhesion molecule-1, important in growth and inflammation. Conclusions : Human ECs possess functionally active Nox5, regulated by Ang II and ET-1 through Ca 2+ /calmodulin-dependent, Rac-1-independent mechanisms. Nox5 activation by Ang II and ET-1 induces ROS generation and ERK1/2 phosphorylation. Nox5 is involved in ERK1/2-regulated growth and inflammatory signaling by Ang II but not by ET-1. We elucidate novel mechanisms whereby vasoactive peptides regulate Nox5 in human ECs and demonstrate differential Nox5-mediated functional responses by Ang II and ET-1. Such phenomena link Ca 2+ /calmodulin to Nox5 signaling, potentially important in the regulation of endothelial function by Ang II and ET-1.
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NO functions in mammalian systems extend beyond vascular signaling and are relevant in all organ systems, including neuronal signaling and host defense.
“The functions of NO in mammalian systems extend beyond vascular signaling and are relevant in all organ systems, including but not limited to neuronal signaling, and host defense”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [659]
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References 48 · Cited by 188
- Authors
- Montezano, A. C., Burger, D., Paravicini, T. M., Chignalia, A. Z., Yusuf, H., Almasri, M., He, Y., Callera, G. E., He, G., Krause, K.-H., Lambeth, D., Quinn, M. T., & Touyz, R. M.
- Affiliations
- University of Geneva (CH)
- From the Kidney Research Centre (A.C.M., D.B., T.M.P., A.Z.C., H.Y., M.A., Y.H., G.E.C., G.H., R.M.T.), Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada; Department of Genetic and Laboratory Medicine, Geneva University Hospitals, and Department of Pathology and Immunology, University of Geneva, Faculty of Medicine (K.-H.K.), Geneva, Switzerland; Department of Pathology Laboratory Medicine (D.L.), Emory University School of Medicine, Atlanta, Georgia; and Department of...
- ORCID
- Venue
- Circulation Research
- Published
- 2010-04-30
- Volume
- 106
- Issue
- 8
- Pages
- 1363-1373
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3119893
- OpenAlex
- W1966748010
- Cited by
- 188
- References
- 48
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 7 · 2021: 12 · 2020: 14 · 2019: 12 · 2018: 12 · 2017: 5 · 2016: 10 · 2015: 11 · 2014: 15 · 2013: 13 · 2012: 34
- FWCI
- 13.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Canadian Institutes of Health Research (44018)
- National Institute of General Medical Sciences (P30GM110732)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR042426)
- National Center for Research Resources (P20RR020185)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- NADPH oxidase, angiotensin II, endothelin-1, calcium/calmodulin signaling, superoxide production, ERK1/2 phosphorylation, mitogen-activated protein kinase, endothelial cell proliferation, VCAM-1, proliferating cell nuclear antigen, oxidative stress, inflammation, diltiazem
- MeSH terms
- NADPH Oxidase 5, Angiotensin II, Calcium, Calcium Channel Blockers, Calmodulin, Cells, Cultured, Diltiazem, Enzyme Activation, Enzyme Inhibitors, Humans, Imidazoles, Inflammation, Membrane Proteins, Phosphorylation, Pyrones, Quinolines, RNA, Messenger, Superoxides, Time Factors, Signal Transduction, Gene Expression Regulation, Enzymologic, Proliferating Cell Nuclear Antigen, Vascular Cell Adhesion Molecule-1, NADPH Oxidases, Endothelin-1, Mitogen-Activated Protein Kinase 1, rac1 GTP-Binding Protein, RNA Interference, Endothelial Cells, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3
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