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Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy.
Am J Pathol. 2000 Jul; 157(1):111-22.AJ

Abstract

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.

Authors+Show Affiliations

Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10880382

Citation

Müller, D N., et al. "Angiotensin II (AT(1)) Receptor Blockade Reduces Vascular Tissue Factor in Angiotensin II-induced Cardiac Vasculopathy." The American Journal of Pathology, vol. 157, no. 1, 2000, pp. 111-22.
Müller DN, Mervaala EM, Dechend R, et al. Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. Am J Pathol. 2000;157(1):111-22.
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. (2000). Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. The American Journal of Pathology, 157(1), 111-22.
Müller DN, et al. Angiotensin II (AT(1)) Receptor Blockade Reduces Vascular Tissue Factor in Angiotensin II-induced Cardiac Vasculopathy. Am J Pathol. 2000;157(1):111-22. PubMed PMID: 10880382.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. AU - Müller,D N, AU - Mervaala,E M, AU - Dechend,R, AU - Fiebeler,A, AU - Park,J K, AU - Schmidt,F, AU - Theuer,J, AU - Breu,V, AU - Mackman,N, AU - Luther,T, AU - Schneider,W, AU - Gulba,D, AU - Ganten,D, AU - Haller,H, AU - Luft,F C, PY - 2000/7/6/pubmed PY - 2000/8/12/medline PY - 2000/7/6/entrez SP - 111 EP - 22 JF - The American journal of pathology JO - Am J Pathol VL - 157 IS - 1 N2 - 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. SN - 0002-9440 UR - https://www.unboundmedicine.com/medline/citation/10880382/Angiotensin_II__AT_1___receptor_blockade_reduces_vascular_tissue_factor_in_angiotensin_II_induced_cardiac_vasculopathy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(10)64523-3 DB - PRIME DP - Unbound Medicine ER -