Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor inangiotensin II-induced cardiac vasculopathy

Tissue factor (TF), a main initiator of clotting, is upregulated in vasculo pathy, We tested the hypothesis that chronic in vivo angiotensin (ANG) II r eceptor AT, receptor blockade inhibits TF expression in a model of ANG II-i nduced cardiac vasculopathy. Furthermore, we explored the mechanisms by exa mining transcription factor activation and analyzing the TF promoter. Untre ated transgenic rats overexpressing the human renin and angiotensinogen gen es (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 pre vented 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 cor onary artery smooth muscle cells and Chinese hamster ovary cells overexpres sing the AT, receptor with plasmids containing the human TF promoter and th e luciferase reporter gene. ANG II induced the full-length TF promoter in b oth 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 reduc ed transcription. Thus, the present study clearly shows atl aberrant TF exp ression in the endothelium and media in rats with ANG II-induced vasculopat hy. The beneficial effects of BT, receptor blockade in this model are media ted via the inhibition of NF-kappa B and AP-1 activation, thereby preventin g TF expression, cardiac vasculopathy, and microinfarctions.