Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV

Recent studies from this laboratory have demonstrated that angiotensin II (Ang II) stimulates the expression of plasminogen activator inhibitor I (PAI- 1) in cultured endothelial cells. This response does not appear to be mediated via an interaction with either the AT₁ or the AT₂ receptor subtype. Since a novel angiotensin receptor has been identified in a variety of tissues that specifically binds the hexapeptide Ang IV (Ang II, [3-8]), we therefore examined the effects of Ang IV on the expression of PAI-1 mRNA in bovine aortic endothelial cells. Ang IV stimulated dose- and time-dependent increases in the expression of PAI-1 mRNA. The effect of Ang IV (10 nM) was not inhibited by Dup 753 (1.0 μM), a highly specific antagonist of the AT₁ receptor, or by PD123177 (1.0 μM), a highly specific antagonist of the AT₂ receptor. In contrast, the AT₄ receptor antagonist, WSU1291 (1.0 μM), effectively prevented PAI-1 expression. Although larger forms of angiotensin (i.e., Ang I, Ang II, and Ang III) are capable of inducing PAI-1 expression, this property is lost in the presence of converting enzyme or aminopeptidase inhibitors. These results indicate that the hexapeptide Ang IV is the form of angiotensin that stimulates endothelial expression of PAI-1. This effect appears to be mediated via the stimulation of an endothelial receptor that is specific for Ang IV.