Increased expression of plasminogen activator inhibitor-1 by mediators of the acute phase response: a potential progenitor of vasculopathy in hypertensives.
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)-1beta, and IL-6, on PAI-1 production in a human hepatoma cell line, HepG2. IL-1beta (1 ng/ml) and IL-6 (1 ng/ml) increased the accumulation of PAI-1 in the conditioned media over 24 h (IL-1beta: 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, 10 micromol/l) attenuated the PAI-1 production induced by IL-1beta 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-1beta 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.
Dong
Jie
J
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Fujii
Satoshi
S
Goto
Daisuke
D
Furumoto
Tomoo
T
Kaneko
Takeaki
T
Zaman
Tarkikuz A
TA
Nakai
Yukihito
Y
Mishima
Tetsuya
T
Imagawa
Shogo
S
Kitabatake
Akira
A
D000210:Acute-Phase Reaction; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000150:complications / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C012258:mevastatin; D008148:Lovastatin; D008798:Mevalonic Acid