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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.
Circ Res 2010; 106(8):1363-73CircR

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.

Authors+Show Affiliations

Kidney Research Centre, University of Ottawa, 451 Smyth Rd, Ottawa, K1H 8M5, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20339118

Citation

Montezano, Augusto 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." Circulation Research, vol. 106, no. 8, 2010, pp. 1363-73.
Montezano AC, Burger D, Paravicini TM, 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. Circ Res. 2010;106(8):1363-73.
Montezano, A. C., Burger, D., Paravicini, T. M., Chignalia, A. Z., Yusuf, H., Almasri, M., ... Touyz, R. M. (2010). 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. Circulation Research, 106(8), pp. 1363-73. doi:10.1161/CIRCRESAHA.109.216036.
Montezano AC, 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. Circ Res. 2010 Apr 30;106(8):1363-73. PubMed PMID: 20339118.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Montezano,Augusto C, AU - Burger,Dylan, AU - Paravicini,Tamara M, AU - Chignalia,Andreia Z, AU - Yusuf,Hiba, AU - Almasri,Mahmoud, AU - He,Ying, AU - Callera,Glaucia E, AU - He,Gang, AU - Krause,Karl-Heinz, AU - Lambeth,David, AU - Quinn,Mark T, AU - Touyz,Rhian M, Y1 - 2010/03/25/ PY - 2010/3/27/entrez PY - 2010/3/27/pubmed PY - 2010/5/25/medline SP - 1363 EP - 73 JF - Circulation research JO - Circ. Res. VL - 106 IS - 8 N2 - 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. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/20339118/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_ L2 - http://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.109.216036?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -