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 demonstrate s a significant concentration-dependent stimulatory effect of LDL on hepato cyte growth factor (HGF) synthesis (maximum release: 423 +/- 16% of control ) and HGF receptor mRNA expression in cultured human coronary artery endoth elial 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 upreg ulated 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 k inase activity of the HGF receptor c-met, since it was antagonized by the t yrosine kinase inhibitor lavendustin A. In addition, HGF also significantly reduced the LDL-stimulated ET-1 release. The LDL-induced upregulation of H GF synthesis in HCAEC and the inhibitory effect of HGF on ET-1 synthesis su ggest a protective role of HGF in coronary atherosclerosis.