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Title

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
Authors
Montezano, A. C.
Burger, Dylan
Paravicini, T. M.
Chignalia, A. Z.
Yusuf, Hiba
Almasri, Mahmoud
He, Ying
Callera, G. E.
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Published in Circulation Research. 2010, vol. 106, no. 8, p. 1363-1373
Abstract 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.
Keywords Angiotensin II/ metabolism — Calcium/ metabolism — Calcium Channel Blockers/pharmacology — Calmodulin/antagonists & inhibitors/ metabolism — Cells, Cultured — Diltiazem/pharmacology — Endothelial Cells/drug effects/ enzymology — Endothelin-1/ metabolism — Enzyme Activation — Enzyme Inhibitors/pharmacology — Gene Expression Regulation, Enzymologic — Humans — Imidazoles/pharmacology — Inflammation/enzymology — JNK Mitogen-Activated Protein Kinases/metabolism — Membrane Proteins/genetics/ metabolism — Mitogen-Activated Protein Kinase 1/metabolism — Mitogen-Activated Protein Kinase 3/metabolism — NADPH Oxidase/genetics/ metabolism — Phosphorylation — Proliferating Cell Nuclear Antigen/metabolism — Pyrones/pharmacology — Quinolines/pharmacology — RNA Interference — RNA, Messenger/metabolism — Signal Transduction/drug effects — Superoxides/metabolism — Time Factors — Vascular Cell Adhesion Molecule-1/metabolism — p38 Mitogen-Activated Protein Kinases/metabolism — rac1 GTP-Binding Protein/antagonists & inhibitors/ metabolism
Identifiers
PMID: 20339118
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Other version: http://circres.ahajournals.org/cgi/reprint/106/8/1363.pdf
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(ISO format) 		MONTEZANO, A. C. et al. 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. In: Circulation Research, 2010, vol. 106, n° 8, p. 1363-1373. https://archive-ouverte.unige.ch/unige:11479

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Deposited on : 2010-08-27

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