The role of hepatocyte growth factor in atherosclerosis
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Hepatocyte growth factor (HGF) has multiple effects on target cells upon activation of its receptor, c-met. We demonstrated by immunohistochemistry that HGF and c-met are expressed in human atherosclerotic lesions by monocytes, SMC and by endothothelial cells in neovascularized regions of the plaque. However, its role in atherosclerosis has not been fully studied. We examined the effect of HGF treatment on both endothelial cells and smooth muscle cells (SMC), both of which express c-met, as these cells types play important roles in atherosclerosis. Both endothelial cell apoptosis and SMC migration are involved in the pathogenesis and progression of atherosclerosis and therefore we examined the effects of HGF on these two processes. In endothelial cells, HGF induces migration, proliferation, and angiogenesis. We determined that HGF is also anti-apoptotic for human endothelial cells, and identified the signaling pathways by which it mediates its effects. Human umbilical vein endothelial cells (HUVEC) were deprived of serum, resulting in apoptosis that was significantly inhibited in a dose dependent manner by the addition of HGF. Akt and ERK1/2, cell survival molecules, were phosphorylated by HGF treatment of HUVEC in a time dependent manner. Inhibition of Akt and ERK1/2 activation abolished the anti-apoptotic effects of HGF. Another regulator of apoptosis is NF-kappaB. However, HGF did not induce NF-kappaB translocation to the nucleus, suggesting that NF-kappaB is not involved in the anti-apoptotic effects of HGF. To study the mechanisms of HGF-induced SMC migration, we developed a migration assay in which SMC are plated onto gelatin-coated tissue culture inserts and allowed to migrate in response to HGF. Inhibitory antibodies to integrins were used to determine which integrins mediated HGF-induced SMC migration. We found that inhibition of beta1 or beta3 integrins resulted in a significant decrease in SMC migration. In addition, HGF induced the redistribution of focal adhesions in SMC along with activation of focal adhesion kinase and proline-rich tyrosine kinase 2. When SMC were pretreated with genestein, a tyrosine kinase inhibitor, as well as inhibitors to the PI3-K, ERK1/2, and p38-MAPK signal transduction pathways, we found that inhibition of all three pathways reduced SMC migration to HGF, indicating their importance in HGF mediated SMC migration. (Abstract shortened by UMI.).