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

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)-α 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 (AT ₂R) receptors, and the production and release of TNF-α and MMP-2 were assessed. ANG II increased TNF-α mRNA and protein expression and the release of bioactive TNF-α. 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-α could mediate the effects of ANG II on MMP-2 release, cells were pretreated with anti-TNF-α neutralizing antibodies or pentoxifylline (an inhibitor of TNF-α synthesis). TNF-α inhibition prevented the secretion of MMP-2 induced by ANG II. Furthermore, AT₂R antagonism with candesartan prevented the formation of MMP-2 and TNF-α and the reduction of TIMP-2 induced by ANG II. These results indicate that ANG II, via AT₁R, modulates the secretion of TNF-α and MMP-2 from endothelial cells and that TNF-α mediates the effects of ANG II on MMP-2 release.