Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy.
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.
Müller
D N
DN
Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Mervaala
E M
EM
Dechend
R
R
Fiebeler
A
A
Park
J K
JK
Schmidt
F
F
Theuer
J
J
Breu
V
V
Mackman
N
N
Luther
T
T
Schneider
W
W
Gulba
D
D
Ganten
D
D
Haller
H
H
Luft
F C
FC
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001779:Blood Coagulation Factors / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D003327:Coronary Disease / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D039041:Integrin alpha4beta1; D016023:Integrins / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D016201:Receptors, Lymphocyte Homing / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013925:Thromboplastin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014655:Vascular Resistance / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001779:Blood Coagulation Factors; D016326:Extracellular Matrix Proteins; D039041:Integrin alpha4beta1; D016023:Integrins; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D016201:Receptors, Lymphocyte Homing; D013777:Tetrazoles; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D000068756:Valsartan; D013925:Thromboplastin; D014633:Valine