(Hypertension. 2000;36:282.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Effect of Bosentan on NF-
B, Inflammation, and Tissue Factor in Angiotensin II–Induced End-Organ Damage
From Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany (D.N.M., E.M.A.M., F.S., J.-K.P., R.D., E.G., W.S., F.C.L.); the Institute of Biomedicine, University of Helsinki, Finland (E.M.A.M.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (D.G.); Medizinische Hochschule Hannover, Hannover, Germany (H.H.); and Hoffmann-La Roche, Basel, Switzerland (V.B., B.-M.L.).
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de
Abstract—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)-
B and AP-1 expression in the kidney and heart; the p65 NF-B
subunit was increased in the endothelium, vascular
smooth muscles cells, infiltrating cells, glomeruli, and tubules. In
the heart and kidney, ETA/B receptor blockade inhibited
NF-B 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, ETA/B receptor blockade inhibits NF-B
and AP-1 activation and the NF-B– 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-B and AP-1 activation and subsequent inflammation and coagulation
involve at least in part the ETA/B receptors.
Key Words: angiotensin I • endothelin • genes • albuminuria • renin-angiotensin system
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