Increased Expression of Plasminogen Activator Inhibitor-1 by Mediators of the Acute Phase Response: a Potential Progenitor of Vasculopathy in Hypertensives

Abstract

Hypertension is an important risk factor for coronary atherosclerosis, which is accelerated by inflammation and diminished fibrinolysis. We have previously shown that levels of plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of fibrinolysis, are increased with atherogenic metabolic derangement. Because the liver is one of the major sources of circulating PAI-1, we here examined the effects of two proinflammatory cytokines, interleukin (IL)-1β and IL-6, on PAI-1 production in a human hepatoma cell line, HepG2. IL-1β (1 ng/ml) and IL-6 (1 ng/ml) increased the accumulation of PAI-1 in the conditioned media over 24 h (IL-1β: 2.1±0.2 (mean±SD) fold over the control; IL-6:1.4±0.2 fold; Western blot, p <0.05). The increase in PAI-1 protein accumulation correlated with the increased expression of PAI-1 mRNA (Northern blot). An HMG-CoA reductase inhibitor (mevastatin, 10μmol/l) attenuated the PAI-1 production induced by IL-1β and IL-6. The plasma PAI-1 activity level was higher in hypertensives than in normotensives (10.0±9.8 AU/ml vs. 6.2±4.5 AU/ml, p <0.05). The plasma PAI-1 antigen level was also higher in hypertensives than in normotensives (30.9±22.4 ng/ml vs. 24.4±13.3 ng/ml, p <0.05). Thus, 1) IL-1β and IL-6 can increase PAI-1 production in hepatic cells and 2) mevastatin may exert anti-thrombotic effects by decreasing the PAI-1 protein production induced by these proinflammatory cytokines. These results provide further insights into how inflammation is involved in the atherothrombotic complications observed in hypertensives, which may be ameliorated by HMG-CoA reductase inhibitors. (Hypertens Res 2003; 26: 723-729)