Effect of bosentan on NF-kappa B, 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 invo lved are uncertain. We tested the hypothesis that endothelin (ET)(A/B) rece ptor blockade with bosentan (100 mg/kg by gavage after age 4 weeks) amelior ates cardiac and renal damage by decreasing inflammation in rats harboring both human renin and angiotensinogen genes (dTGR). Furthermore, we elucidat ed the effect of bosentan on tissue factor (TF), which is a key regulator o f the extrinsic coagulation cascade. We compared bosentan with hydralazine (80 mg/L in the drinking water for 3 weeks) as a blood pressure control. Un treated dTGR featured hypertension, focal necrosis in heart and kidney, and a 45% mortality rate (9 of 20) at age 7 weeks. Compared with Sprague-Dawle y controls, both systolic blood pressure and 24-hour albuminuria were incre ased 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 red uced blood pressure and cardiac hypertrophy. Mortality rate was markedly re duced 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)-kappa B and AP-1 express ion in the kidney and heart; the p65 NF-kappa B subunit was increased in th e endothelium, vascular smooth muscles cells, infiltrating cells, glomeruli , and tubules. In the heart and kidney, ETA/B receptor blockade inhibited N F-kappa B and AP-1 activation compared with hydralazine treatment. Macropha ge infiltration, ICAM-1 expression, and the integrin expression on infiltra ting cells were markedly reduced. Renal vasculopathy was accompanied by inc reased 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-kappa B and AP-1 activation and the NF-ka ppa B- and/or AP-1-regulated genes ICAM-1, VCAM-1, and TF, independent of b lood pressure-related effects. We conclude that Ang II-induced NF-kappa B a nd AP-1 activation and subsequent inflammation and coagulation involve at l east in part the ETA/B receptors.