Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production

Abstract

Recent data suggest an interaction between the renin-angiotensinaldosterone system and fibrinolysis. Although previous work has focused on the effect of angiotensin II (Aug 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 Aug 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 Aug 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 Aug II and aldosterone was observed in cultured human umbilical vein endothelial cells. The time course of the effect of aldosterone on Aug 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 Aug II on PAI-1 expression in vitro and in viva in humans.