Angiotensin II and IV stimulate expression and release of plasminogen activator inhibitor-1 in cultured human coronary artery endothelial cells

There is increasing evidence that angiotensin 11 influences thrombogenesis by regulating the expression of plasminogen activator inhibitor-1 (PAI-1). In this study, the effects of angiotensin 11 and its receptors on the expression and release of PAI-1 and tissue-type plasminogen activator (t-PA) were examined in human coronary artery endothelial cells (HCAECs). As control, cells were treated with angiotensin IV. HCAECs incubated with angiotensin 11 increased the expression of PAI-1 mRNA in a concentration (10(-9)-10(-5) M)- and time (6-24 h)-dependent manner. PAI-1 protein release was also increased in the culture medium of HCAECs treated with angiotensin It. The effects of angiotensin 11 (10(-6) M) were blocked completely by the AT, receptor blocker losartan (10(-6) M) but not by the AT(2) receptor blocker PD 123319 (10(-6) AT). Angiotensin 11 pretreatment also slightly, but significantly, increased t-PA mRNA expression. This effect of angiotensin 11 on t-PA mRNA was blocked by losartan but not by PD123319. HCAECS treated with angiotensin 11 revealed large amounts of the lipid peroxidation product, malonaldehyde (MDA). The effects of angiotensin 11 on PAI-1 expression and NIDA release were blocked by pretreatment of cells with alpha-tocopherol (10(-5) M). In control experiments, treatment of HCAECs with angiotensin IV markedly increased PAI-1 mRNA expression and protein release. This effect of angiotensin IV was blocked by the AT, receptor blocker divalinal (10(-6) AT). These observations indicate that AT, receptor activation plays an important role in the stimulation of PAI-1 expression and release in response to angiotensin II. Upregulation of t-PA gone may reflect autoregulation in response to PAI-1 release. Angiotensin II-mediated activation of oxidation pathways may relate to uupregulation of PAI-1. This study also confirms that angiotensin IV upregulates PAI-1 expression in HCAECs.