Oxidized LDL inhibit hepatocyte growth factor synthesis in coronary smooth muscle cells☆

Hepatocyte growth factor (HGF) is a potent regeneration factor for endothelial and epithelial cells, and has also been shown to modulate extracellular matrix synthesis and matrix metalloproteinase activity in renal epithelial cells and tumor cells. Controversial results have been published concerning the possible role of HGF in the pathogenesis of coronary atherosclerosis. In this study, we have investigated the effect of oxidized low density lipoproteins (LDL) and elevated glucose concentrations on HGF synthesis in cultured human coronary artery smooth muscle cells. In addition, we have studied whether HGF modulates the release of extracellular matrix, extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinases (MMP) by coronary artery smooth muscle cells. Oxidized LDL (1–10 μg/ml) induced a significant dose-dependent decrease of HGF release and a concomitant decrease of HGF mRNA expression, whereas native LDL and elevated glucose concentrations induced no significant changes of HGF synthesis. Incubation of cultured human coronary smooth muscle cells with human HGF (1–100 ng/ml) did not significantly alter cell migration and collagen I, fibronectin, EMMPRIN, MMP-1, MMP-2 and MMP-9 release. In summary, our results provide evidence that HGF does not promote coronary plaque growth or plaque destabilization. Regarding the fact that HGF is a potent endothelial cell regeneration factor, the observed downregulation of HGF synthesis by oxidized LDL supports the concept that HGF might be a protective factor in coronary atherosclerosis and that a decrease rather than an increase of HGF synthesis might promote coronary atherosclerosis.

Keywords: Atherosclerosis, Hepatocyte growth factor, Low density lipoproteins, Extracellular matrix, Matrix metalloproteinases