Role of the angiotensin AT(1) receptor in rat aortic and cardiac PAI-1 gene expression

Although the renin-angiotensin system has been implicated in increasing pla sminogen activator inhibitor-1 (PAI-1) expression, the role of the angioten sin type 1 (AT(1)) receptor is controversial. This report examines the effe cts of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT(1) antagonism on rat aortic and cardiac PAI-1 gene expression, In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg(2)-Phe(8) (Ang III) were potent agonists of PAI-1 mRNA expression in rat aortic smooth muscle cells (RASMCs), and stimulation of PAI-1 by these peptides was blocked by the AT( 1) antagonist candesartan. Angiotensin Val(3)-Phe(8) (Ang IV) and angiotens in Asp(1)-Pro(7) (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fo ld (P<0.01), and this response was completely blocked by AT(1) receptor ant agonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rat s for 3 hours increased aortic and cardiac PAI-1 mRNA expression by 17- and 9 fold, respectively, and these Ang II responses were completely blocked b y coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were co mpared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expr ession in the aorta and heart from spontaneously hypertensive rats was 5.8- fold and 2-fold higher, respectively, than in control Wistar-Kyoto rats (P< 0.05), Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 ex pression in spontaneously hypertensive rats by 94% and 72%, respectively (P <0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. Thes e results demonstrate a role for the AT(1) receptor in mediating the effect s of Ang II, on aortic and cardiac PAI-1 gene expression.