Key result
Angiotensin II-stimulated PAI-1 (P<0.001) and ppET-1 expression (P=0.01) was diminished in the heart of aldosterone synthase-deficient mice compared to wild-type mice.
Endogenous aldosterone mediates the acute stimulatory effect of Angiotensin II on profibrotic gene expression (PAI-1 and ppET-1) in the heart, but not in the aorta.
Endogenous aldosterone may drive cardiac profibrotic signaling; leaves open whether synthase inhibition alters human fibrosis.
To test the hypothesis that angiotensin (Ang) II induces profibrotic gene expression through endogenous aldosterone, we measured the effect of 4 h infusion (600 ng/kg x min) of Ang II on tissue mRNA expression of plasminogen activator inhibitor 1 (PAI-1), preproendothelin-1 (ppET-1), TGF-beta, and osteopontin in wild-type (WT), aldosterone synthase-deficient (AS(-/-)), and AS(-/-) mice treated with aldosterone (either 500 ng/d for 7 d or 250 ng as a concurrent 4 h infusion). Ang II increased aldosterone in WT (P < 0.001) but not in AS(-/-) mice. Aldosterone (7 d) normalized basal aldosterone concentrations in AS(-/-) mice; however, there was no further effect of Ang II on aldosterone (P = NS). Basal cardiac and aortic PAI-1 and ppET-1 expression were similar in WT and AS(-/-) mice. Ang II-stimulated PAI-1 (P < 0.001) and ppET-1 expression (P = 0.01) was diminished in the heart of AS(-/-) mice; treatment with aldosterone for 4 h or 7 d restored PAI-1 and ppET-1 mRNA responsiveness to Ang II in the heart. Ang II increased PAI-1 (P = 0.01) expression in the aorta of AS(-/-) as well as WT mice. In the kidney, basal PAI-1, ppET-1, and TGF-beta mRNA expression was increased in AS(-/-) compared with WT mice and correlated with plasma renin activity. Ang II did not stimulate osteopontin or TGF-beta expression in the heart or kidney. Endogenous aldosterone contributes to the acute stimulatory effect of Ang II on PAI-1 and ppET-1 mRNA expression in the heart; renin activity correlates with basal profibrotic gene expression in the kidney.
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Luther et al. (2008) studied this question. Angiotensin II infusion vs. Wild-type vs aldosterone synthase-deficient mice was evaluated on Tissue mRNA expression of PAI-1, ppET-1, TGF-beta, and osteopontin (p=<0.001). Angiotensin II-stimulated PAI-1 (P<0.001) and ppET-1 expression (P=0.01) was diminished in the heart of aldosterone synthase-deficient mice compared to wild-type mice.
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