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Rac2 GTPase activation by angiotensin II is modulated by Ca2+/calcineurin and mitogen-activated protein kinases in human neutrophils

By Rajaa El Bekay, Gonzalo Alba Jiménez, María Edith Reyes Quiroz, Pedro Chacón Fernández, Antonio Vega Rioja, José Martín-Nieto, Juan Jiménez Carrasco, Eladio Ramos González-Serna, Josefina Oliván Martínez, Elizabeth Pintado Sanjuan and Francisco Sobrino Beneyto

Abstract

Angiotensin II (Ang II) highly stimulates superoxide anion production by neutrophils. The G-protein Rac2 modulates the activity of NADPH oxidase in response to various stimuli. Here, we describe that Ang II induced both Rac2 translocation from the cytosol to the plasma membrane and Rac2 GTP-binding activity. Furthermore, Clostridium difficile toxin A, an inhibitor of the Rho-GTPases family Rho, Rac and Cdc42, prevented Ang II-elicited O2/ROS production, phosphorylation of the mitogen-activated protein kinases (MAPKs) p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2, and Rac2 activation. Rac2 GTPase inhibition by C. difficile toxin A was accompanied by a robust reduction of the cytosolic Ca2+ elevation induced by Ang II in human neutrophils. Furthermore, SB203580 and PD098059 act as inhibitors of p38MAPK and ERK1/2 respectively, wortmannin, an inhibitor of phosphatidylinositol-3-kinase, and cyclosporin A, a calcineurin inhibitor, hindered both translocation of Rac2 from the cytosol to the plasma membrane and enhancement of Rac2 GTP-binding elicited by Ang II. These results provide evidence that the activation of Rac2 by Ang II is exerted through multiple signalling pathways, involving Ca2+/calcineurin and protein kinases, the elucidation of which should be insightful in the design of new therapies aimed at reversing the inflammation of vessel walls found in a number of cardiovascular diseases.This work was financed by grants from the Ministerio de Educación y Ciencia (BFU2006-13802), and the Consejería de Innovación, Ciencia y Empresa (P06-CTS-1936), Junta de Andalucía, Spain, awarded to F S

Topics: Rac2 GTPase activation, Angiotensin II, Ca2+/calcineurin, Mitogen-activated protein kinases, Human neutrophils, Fisiología, Bioquímica y Biología Molecular
Publisher: Society for Endocrinology
Year: 2007
DOI identifier: 10.1677/JME-07-0074
OAI identifier: oai:rua.ua.es:10045/9719

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