Effect of bosentan on NF-kappaB, inflammation, and tissue factor in angiotensin II-induced end-organ damage.
Reports on the effectiveness of endothelin receptor blockers in angiotensin (Ang) II-induced end-organ damage are conflicting, and the mechanisms involved are uncertain. We tested the hypothesis that endothelin (ET)(A/B) receptor blockade with bosentan (100 mg/kg by gavage after age 4 weeks) ameliorates cardiac and renal damage by decreasing inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). Furthermore, we elucidated the effect of bosentan on tissue factor (TF), which is a key regulator of the extrinsic coagulation cascade. We compared bosentan with hydralazine (80 mg/L in the drinking water for 3 weeks) as a blood pressure control. Untreated dTGR featured hypertension, focal necrosis in heart and kidney, and a 45% mortality rate (9 of 20) at age 7 weeks. Compared with Sprague-Dawley controls, both systolic blood pressure and 24-hour albuminuria were increased in untreated dTGR (203+/-8 versus 111+/-2 mm Hg and 67.1+/-8.6 versus 0.3+/-0.06 mg/d at week 7, respectively). Bosentan and hydralazine both reduced blood pressure and cardiac hypertrophy. Mortality rate was markedly reduced by bosentan (1/15) and partially by hydralazine (4/15). However, only bosentan decreased albuminuria and renal injury. Untreated and hydralazine-treated dTGR showed increased nuclear factor (NF)-kappaB and AP-1 expression in the kidney and heart; the p65 NF-kappaB subunit was increased in the endothelium, vascular smooth muscles cells, infiltrating cells, glomeruli, and tubules. In the heart and kidney, ET(A/B) receptor blockade inhibited NF-kappaB and AP-1 activation compared with hydralazine treatment. Macrophage infiltration, ICAM-1 expression, and the integrin expression on infiltrating cells were markedly reduced. Renal vasculopathy was accompanied by increased tissue factor expression on macrophages and vessels of untreated and hydralazine-treated dTGR, which was markedly reduced by bosentan. Thus, ET(A/B) receptor blockade inhibits NF-kappaB and AP-1 activation and the NF-kappaB- and/or AP-1-regulated genes ICAM-1, VCAM-1, and TF, independent of blood pressure-related effects. We conclude that Ang II-induced NF-kappaB and AP-1 activation and subsequent inflammation and coagulation involve at least in part the ET(A/B) receptors.
Muller
D N
DN
Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Mervaala
E M
EM
Schmidt
F
F
Park
J K
JK
Dechend
R
R
Genersch
E
E
Breu
V
V
Löffler
B M
BM
Ganten
D
D
Schneider
W
W
Haller
H
H
Luft
F C
FC
D000419:Albuminuria / Q000517:prevention & control; D000804:Angiotensin II / Q000009:adverse effects; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D005353:Fibronectins / Q000032:analysis; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D013925:Thromboplastin / Q000187:drug effects* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D000959:Antihypertensive Agents; D005353:Fibronectins; D016328:NF-kappa B; D013449:Sulfonamides; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; D000808:Angiotensinogen; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D006830:Hydralazine; D013925:Thromboplastin; D012083:Renin; D000077300:Bosentan