Increased Expression of Plasminogen Activator Inhibitor-1 by Mediators of the Acute Phase Response: a Potential Progenitor of Vasculopathy in Hypertensives
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<B>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, <I>p</I> <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 <I>vs</I>. 6.2±4.5 AU/ml, <I>p</I> <0.05). The plasma PAI-1 antigen level was also higher in hypertensives than in normotensives (30.9±22.4 ng/ml <I>vs</I>. 24.4±13.3 ng/ml, <I>p</I> <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. (<I>Hypertens Res </I>2003; 26: 723-729)</B>
- 日本高血圧学会の論文
日本高血圧学会 | 論文
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