Müller D N, Mervaala E M, Dechend R, Fiebeler A, Park J K, Schmidt F, Theuer J, Breu V, Mackman N, Luther T, Schneider W, Gulba D, Ganten D, Haller H, Luft F C
Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Am J Pathol. 2000 Jul;157(1):111-22. doi: 10.1016/S0002-9440(10)64523-3.
Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT(1) 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 II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-kappaB 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(1) 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(1) receptor blockade. Deletion of both AP-1 and NF-kappaB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT(1) receptor blockade in this model are mediated via the inhibition of NF-kappaB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microinfarctions.
组织因子（TF）是凝血的主要启动因子，在血管病变中上调。我们检验了以下假设：在血管紧张素（ANG）II诱导的心脏血管病变模型中，慢性体内血管紧张素II受体AT1受体阻断可抑制TF表达。此外，我们通过检查转录因子激活情况和分析TF启动子来探究其机制。未治疗的过表达人肾素和血管紧张素原基因的转基因大鼠（dTGR）表现为高血压和严重的左心室肥厚，并伴有局灶性坏死区域，7周龄时死亡。与Sprague-Dawley大鼠相比，血浆和心脏中的ANG II增加了三到五倍。缬沙坦慢性治疗可使血压和冠状动脉阻力完全恢复正常，并改善心脏肥厚（P<0.001）。缬沙坦可防止dTGR心脏中的单核细胞/巨噬细胞浸润、核因子κB（NF-κB）和激活蛋白-1（AP-1）激活以及c-fos表达。NF-κB亚基p65和TF表达在心脏血管的内皮和中膜中增加，而缬沙坦治疗可使其明显降低。为了分析TF转录的机制，我们随后用含有人类TF启动子和荧光素酶报告基因的质粒转染了过表达AT1受体的人冠状动脉平滑肌细胞和中国仓鼠卵巢细胞。ANG II在两种转染细胞系中均诱导全长TF启动子。AT1受体阻断可消除TF转录。同时缺失AP-1和NF-κB位点可完全降低ANG II诱导的TF基因转录，而缺失AP-1位点则会降低转录。因此，本研究清楚地表明，在ANG II诱导的血管病变大鼠中，内皮和中膜中存在异常的TF表达。在该模型中，AT1受体阻断的有益作用是通过抑制NF-κB和AP-1激活介导的，从而防止TF表达、心脏血管病变和微梗死。
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