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Am J Physiol Cell Physiol 286: C779-C784, 2004. First published November 26, 2003; doi:10.1152/ajpcell.00398.2003
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VASCULAR BIOLOGY

Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-{alpha}

Ivan A. Arenas,1,2 Yi Xu,1,2 Patricio Lopez-Jaramillo,3,4 and Sandra T. Davidge1,2

1Department of Obstetrics and Gynecology and 2Department of Physiology, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2; and 3Fundacion Cardiovascular del Oriente and 4Universidad Industrial de Santander, Bucaramanga, Colombia

Submitted 17 September 2003 ; accepted in final form 25 November 2003

Angiotensin II (ANG II) has been etiologically linked to vascular disease; however, its role in the alterations of endothelial function that occur in vascular disorders is not completely understood. Matrix metalloproteinases (MMPs) and proinflammatory cytokines are involved in the pathological remodeling of blood vessels that occurs in vascular disease. In this study we evaluated the effects of ANG II on tumor necrosis factor (TNF)-{alpha} and MMP-2 production in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with ANG II (0.1–10 µM) for 24 h, in the presence or absence of antagonists of ANG II type 1 (AT1R) and type 2 (AT2R) receptors, and the production and release of TNF-{alpha} and MMP-2 were assessed. ANG II increased TNF-{alpha} mRNA and protein expression and the release of bioactive TNF-{alpha}. Moreover, ANG II induced MMP-2 release and reduced the secretion of tissue inhibitor of MMP (TIMP)-2 from endothelial cells. To elucidate whether endogenous TNF-{alpha} could mediate the effects of ANG II on MMP-2 release, cells were pretreated with anti-TNF-{alpha} neutralizing antibodies or pentoxifylline (an inhibitor of TNF-{alpha} synthesis). TNF-{alpha} inhibition prevented the secretion of MMP-2 induced by ANG II. Furthermore, AT1R antagonism with candesartan prevented the formation of MMP-2 and TNF-{alpha} and the reduction of TIMP-2 induced by ANG II. These results indicate that ANG II, via AT1R, modulates the secretion of TNF-{alpha} and MMP-2 from endothelial cells and that TNF-{alpha} mediates the effects of ANG II on MMP-2 release.

remodeling; vasoactive mediators; inflammation



Address for reprint requests and other correspondence: S. T. Davidge, Perinatal Research Centre, 220 HMRC, Univ. of Alberta, Edmonton, AB, Canada T6G 2S2 (E-mail: sandra.davidge{at}ualberta.ca).




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