Role of the angiotensin AT1 receptor in rat aortic and cardiac PAI-1 gene expression

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Abstract

Although the renin-angiotensin system has been implicated in increasing plasminogen activator inhibitor-1 (PAI-1) expression, the role of the angiotensin type 1 (AT1) receptor is controversial. This report examines the effects of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT1 antagonism on rat aortic and cardiac PAI-1 gene expression. In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg2-Phe8 (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 AT1 antagonist candesartan. Angiotensin Val3-Phe8 (Ang IV) and angiotensin Asp1-Pro7 (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fold (P<0.01), and this response was completely blocked by AT1 receptor antagonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rats 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 by coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were compared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expression 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 expression in spontaneously hypertensive rats by 94% and 72%, respectively (P<0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. These results demonstrate a role for the AT1 receptor in mediating the effects of Ang II on aortic and cardiac PAI-1 gene expression.

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Chen, H. C., Bouchie, J. L., Perez, A. S., Clermont, A. C., Izumo, S., Hampe, J., & Feener, E. P. (2000). Role of the angiotensin AT1 receptor in rat aortic and cardiac PAI-1 gene expression. Arteriosclerosis, Thrombosis, and Vascular Biology, 20(10), 2297–2302. https://doi.org/10.1161/01.ATV.20.10.2297

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