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Synergistic Effect of Adrenal Steroids and Angiotensin II on Plasminogen Activator Inhibitor-1 Production¹

Departments of Medicine (N.J.B., K.-S.K., L.S.B., J.H.N., D.E.V.), Pharmacology (N.J.B., K.-S.K., Y.-Q.C., D.E.V.), and Radiology (S.G.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; and Veterans Administration Medical Center, Nashville, Tennessee 37212

Address all correspondence and requests for reprints to: Nancy J. Brown, M.D., 560 MRB-I, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602. E-mail: nancy.brown{at}mcmail.vanderbilt.edu

Recent data suggest an interaction between the renin-angiotensin-aldosterone system and fibrinolysis. Although previous work has focused on the effect of angiotensin II (Ang II) on plasminogen activator inhibitor (PAI-1) expression, the present study tests the hypothesis that aldosterone contributes to the regulation of PAI-1 expression. To test this hypothesis in vitro, luciferase reporter constructs containing the human PAI-1 promoter were transfected into rat aortic smooth muscle cells. Exposure of the cells to 100 nmol/L Ang II resulted in a 3-fold increase in luciferase activity. Neither 1 µmol/L dexamethasone nor 1 µmol/L aldosterone alone increased PAI-1 expression. However, both dexamethasone and aldosterone enhanced the effect of Ang II in a dose-dependent manner. This effect was abolished by mutation in the region of a putative glucocorticoid-responsive element. A similar interactive effect of Ang II and aldosterone was observed in cultured human umbilical vein endothelial cells. The time course of the effect of aldosterone on Ang II-induced PAI-1 expression was consistent with a classical mineralocorticoid receptor mechanism, and the effect of aldosterone on PAI-1 synthesis was attenuated by spironolactone. To determine whether aldosterone affected PAI-1 expression in vivo, we measured local venous PAI-1 antigen concentrations in six patients with primary hyperaldosteronism undergoing selective adrenal vein sampling. PAI-1 antigen, but not tissue plasminogen activator antigen, concentrations were significantly higher in adrenal venous blood than in peripheral venous blood. Taken together, these data support the hypothesis that aldosterone modulates the effect of Ang II on PAI-1 expression in vitro and in vivo in humans.

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