Hepatocyte growth factor is upregulated by low-density lipoproteins and inhibits endothelin-1 release.
Low-density lipoproteins (LDL) are known to cause endothelial injury and to promote the development of atherosclerotic lesions. This study demonstrates a significant concentration-dependent stimulatory effect of LDL on hepatocyte growth factor (HGF) synthesis (maximum release: 423 +/- 16% of control) and HGF receptor mRNA expression in cultured human coronary artery endothelial cells (HCAEC). HGF is a potent mitogen for endothelial cells but does not affect smooth muscle cell proliferation. In contrast, endothelin-1 (ET-1) acts as a mitogen on vascular smooth muscle cells and seems to be upregulated in coronary atherosclerosis. In this study, the basal ET-1 synthesis in HCAEC was concentration-dependently reduced by HGF (minimum: 54 +/- 3% of control). This inhibitory effect seems to be mediated via the tyrosine kinase activity of the HGF receptor c-met, since it was antagonized by the tyrosine kinase inhibitor lavendustin A. In addition, HGF also significantly reduced the LDL-stimulated ET-1 release. The LDL-induced upregulation of HGF synthesis in HCAEC and the inhibitory effect of HGF on ET-1 synthesis suggest a protective role of HGF in coronary atherosclerosis.
Haug
C
C
Institute of Clinical Chemistry, University Hospital Ulm, D-89070 Ulm, Germany. cornelia.haug@medizin.uni-ulm.de
Schmid-Kotsas
A
A
Zorn
U
U
Bachem
M G
MG
Schuett
S
S
Gruenert
A
A
Rozdzinski
E
E
D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism / Q000503:physiopathology; D003331:Coronary Vessels / Q000166:cytology; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis
D019332:Endothelin-1; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met