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

Recent data suggest an interaction between the renin-angiotensin-aldosteron e system and fibrinolysis. Although previous work has focused on the effect of angiotensin II (Ang II) on plasminogen activator inhibitor (PAI-1) expr ession, the present study tests the hypothesis that aldosterone contributes to the regulation of PAI-1 expression. To test this hypothesis in vitro, l uciferase reporter constructs containing the human PAI-1 promoter were tran sfected into rat aortic smooth muscle cells. Exposure of the cells to 100 n mol/L Ang II resulted in a 3-fold increase in luciferase activity. Neither 1 mu mol/L dexamethasone nor 1 mu mol/L aldosterone alone increased PAT-1 e xpression. 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 i nteractive effect of Ang II and aldosterone was observed in cultured human umbilical vein endothelial cells. The time course of the effect of aldoster one on Ang II-induced PAI-1 expression was consistent with a classical mine ralocorticoid receptor mechanism, and the effect of aldosterone on PAI-1 sy nthesis was attenuated by spironolactone. To determine whether aldosterone affected PAI-1 expression in vivo, we measured local venous PAI-1 antigen c oncentrations in six patients with primary hyperaldosteronism undergoing se lective adrenal vein sampling. PAI-1 antigen, but not tissue plasminogen ac tivator 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 exp ression in vitro and in vivo in humans.