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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

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/ metabolismCalcium/ metabolismCalcium Channel Blockers/pharmacologyCalmodulin/antagonists & inhibitors/ metabolismCells, CulturedDiltiazem/pharmacologyEndothelial Cells/drug effects/ enzymologyEndothelin-1/ metabolismEnzyme ActivationEnzyme Inhibitors/pharmacologyGene Expression Regulation, EnzymologicHumansImidazoles/pharmacologyInflammation/enzymologyJNK Mitogen-Activated Protein Kinases/metabolismMembrane Proteins/genetics/ metabolismMitogen-Activated Protein Kinase 1/metabolismMitogen-Activated Protein Kinase 3/metabolismNADPH Oxidase/genetics/ metabolismPhosphorylationProliferating Cell Nuclear Antigen/metabolismPyrones/pharmacologyQuinolines/pharmacologyRNA InterferenceRNA, Messenger/metabolismSignal Transduction/drug effectsSuperoxides/metabolismTime FactorsVascular Cell Adhesion Molecule-1/metabolismp38 Mitogen-Activated Protein Kinases/metabolismrac1 GTP-Binding Protein/antagonists & inhibitors/ metabolism
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PMID: 20339118
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