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Endogenous Aldosterone Contributes to Acute Angiotensin II-Stimulated Plasminogen Activator Inhibitor-1 and Preproendothelin-1 Expression in Heart But Not Aorta

Divisions of Clinical Pharmacology (J.M.L., Z.W., J.M., N.J.B.) and Nephrology and Hypertension (J.M.L.), Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602; and Department of Pathology and Laboratory Medicine (N.M., H.-S.K.), University of North Carolina, Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: James M. Luther, M.D., 560C RRB, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602. E-mail: james.luther{at}vanderbilt.edu.

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 · min) of Ang II on tissue mRNA expression of plasminogen activator inhibitor 1 (PAI-1), preproendothelin-1 (ppET-1), TGF-β, 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-β mRNA expression was increased in AS^–/– compared with WT mice and correlated with plasma renin activity. Ang II did not stimulate osteopontin or TGF-β 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.