(Hypertension. 2001;37:787.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-
B Activation in Angiotensin II–Induced Cardiac Injury
From the Franz Volhard Clinic and Max Delbrück Center, Medical Faculty of the Charité, Humboldt University of Berlin, and Department of Medicine-Nephrology, Hoffmann La Roche Inc, Basel, Schwitzerland; and Hannover Medical School, University of Hannover, Germany.
Correspondence to Dr Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Str 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de
Aldosterone
is implicated in cardiac hypertrophy and fibrosis. We
tested the role of the mineralocorticoid receptor in a model of
angiotensin II–induced cardiac injury. We administered
spironolactone (SPIRO; 20 mg · kg-1
· d-1), valsartan (VAL; 10
mg · kg-1 ·
d-1), or vehicle to rats double transgenic
for the human renin and angiotensinogen genes (dTGR). We
investigated basic fibroblast growth factor (bFGF),
platelet-derived growth factor, transforming growth
factor-ß1, and the transcription factors AP-1
and nuclear factor (NF)-
B. We used immunohistochemistry,
electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated
dTGR developed hypertension, cardiac hypertrophy,
vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks.
SPIRO and VAL prevented death and reversed cardiac
hypertrophy, while only VAL normalized blood pressure. Both
drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR,
whereas platelet-derived growth factor-B and transforming growth
factor-ß1 were little changed. VAL and SPIRO
suppressed this upregulation. Both AP-1 and NF-B were
activated in dTGR compared with controls. VAL and SPIRO reduced
both transcription factors and reduced bFGF, collagen I, fibronectin,
and laminin in the interstitium. These findings show that
aldosterone promotes hypertrophy, cardiac
remodeling, and fibrosis, independent of blood pressure. The effects
involve AP-1, NF-B, and bFGF. Mineralocorticoid receptor blockade
downregulates these effectors and reduces angiotensin
II–induced cardiac damage.
Key Words: angiotensin • nuclear factors • receptors, mineralocorticoid • spironolactone
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