Impact of lysophosphatidylcholine on the plasminogen activator system in cultured vascular smooth muscle cells.
The balance between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolysis. PAI-1 expression increases in atherosclerotic arteries and vascular smooth muscle cells (VSMCs) are one of major constituents of atheroma. We investigated the impact of lysophosphatidylcholine (lysoPC), an active component of oxidized low-density lipoprotein, on the plasminogen activator system of the rat VSMCs. The lysoPC stimulated the protein and gene expressions of PAI-1 but did not affect the protein expression of t-PA. Fibrin overlay zymography revealed that lysoPC increased the activity of PAI-1 in the conditioned media, while concurrently decreasing that of free t-PA. Vitamin E inhibited the lysoPC-induced PAI-1 expression. Further, lysoPC increased the intracellular reactive oxygen species (ROS) formation. Caffeic acid phenethyl ester, an inhibitor of NF-κB, blocked this lysoPC effect. Indeed, lysoPC induced the NF-κB-mediated transcriptional activity as measured by luciferase reporter assay. In addition, genistein, an inhibitor of protein-tyrosine kinase (PTK), diminished the lysoPC effect, while 7,12-dimethylbenz[a]anthracene, a stimulator of PTK, stimulated PAI-1 production. In conclusion, lysoPC does not affect t-PA expression but induces PAI-1 expression in the VSMC by mediating NF-κB and the genistein-sensitive PTK signaling pathways via oxidative stress. Importantly, lysoPC stimulates the enzyme activity of PAI-1 and suppresses that of t-PA.
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. bkyoon@skku.edu
Byung-Koo
BK
Yoon
Young-Hee
YH
Kang
Won-Jong
WJ
Oh
Kyungwon
K
Park
Dong-Yun
DY
Lee
Dooseok
D
Choi
Duk-Kyung
DK
Kim
Youngjoo
Y
Lee
Mee-Ra
MR
Rhyu
D000818:Animals; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D002109:Caffeic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D019833:Genistein / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014810:Vitamin E / Q000494:pharmacology
D001551:Benz(a)Anthracenes; D002109:Caffeic Acids; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D014810:Vitamin E; C046810:7,12-dihydroxymethylbenz(a)anthracene; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D010959:Tissue Plasminogen Activator; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol