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

Abstract

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 microM) for 24 h, in the presence or absence of antagonists of ANG II type 1 (AT(1)R) and type 2 (AT(2)R) 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, AT(1)R 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 AT(1)R, 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.