Angiotensin II (AT1) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy

Tissue factor (TF), a main initiator of clotting, is upregulated in vasculopathy, We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT, receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG IT was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophpy (p < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-KB (NF-kappa B) and activator protein-1 CAP-I) activation, and c-fos expression in dTGR hearts. NF-kappa B subunit p65 and TF expression was Increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT, receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell Lines. TF transcription was abolished by AT, receptor blockade. Deletion of both AP-1 and NF-kappa B sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows atl aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of BT, receptor blockade in this model are mediated via the inhibition of NF-kappa B and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microinfarctions.