Experimental And Clinical Study On The Relationship Between Expression Of Hepatocyte Growth Factor In Monocytes/Macrophages And Stability Of Atherosclerotic Plaques

It is well known that disruption of unstable atherosclerotic plaque with subsequent thrombosis is probably one of the most important mechanisms for the sudden onset of acute coronary syndromes (ACS), including unstable angina(UA), myocardial infarction(AMI), or sudden cardiac death. The composition and tensile strength of the fibrous caps, as well as the activity of abundant monocyte-macrophages infiltrating to the plaques play an important role in determining the stability of the plaques. Many cytokines and growth factors secreted by the activated monocyte-macraphages can induce the activity of proteolytic enzymes, such as a family of matrix metalloproteinases (MMPs). A consensus has been reached that MMPs may weaken the strength of fibrous caps, predisposing it to rupture.Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis of various cells. And c-Met, which is the specific high-affinity receptor of HGF, is encoded by the c-met proto-oncogene. It becomes clear that HGF is a multifunctional growth factor expressed not only in endothelial cells and smooth muscle cells in vascular tissues, but also in immuno-active cells in other organs or tissues. Recent data suggest that HGF/c-Met are involved in the inflammatory process and induced activity of MMPs besides they stimulate angiogenesis of endothelial cells. So we speculated that HGF/c-Met have an important role in the pathogenesis and development of atheroclerosis.The aim of this study is following (1) to examine expression of HGF/c-Met protein in circulating monocytes or macrophages in atherosclerotic plaques afterstimulated by inflammatory cytokines, (2) to explore the possible mechanisms for the changes of plaque stability regulated by HGF, (3) to evaluate if elevated serum HGF can act as an indicator of a ruptured or unstable plaque, (4) to explore a new way to stabilize vulnerable plaques so as to prevent the patients from the onset of ACS.We found that HGF and its specific receptor c-Met were expressed in human peripheral blood monocytes (PBMs) and rat peritoneal macrophages (RPMs) in vitro by hibridization in situ, enzyme-linked immunosorbent assay (ELISA), immunocytochemistry and Western blot, respectively. Inflammatory cytokines such as interleukin-1? and TNFa could promote the expression of HGF/c-Met protein, accompanied with increased expression of MMP-2 protein. All of these effects could be inhibited by suramin, a kind of HGF receptor inhibitor.The immuno-activity of c-Met and TIMP-1 was found in macrophages from human aortic atherosclerotic plaques by immunohistochemistry. However, the immuno-activity of HGF and TNFa were found only in macrophages in ruptured plaques accompanied with weakened expression of TIMP-1.The serial changes of HGF levels in serum and PBMs were determined by ELISA in the patients with ACS. The serum HGF levels in AMI group and UA group were significantly higher than in stable angina pectoris or control group within 24h after the onset of chest pain. Moreover, the elevated serum HGF levels were correlated well with those secreted by PBMs, as well as other inflammatory markers, such as serum TNFa, serum CRP or plasma fibrinogen. The serum HGF levels gradually decreased after the symptoms were abated through 2 weeks of treatment, while serum HGF levels didn't decrease in five patients who died or suffered from AMI in the next 3 months. In addition, it was found that suramin suppressed the production of HGF not only in the PBMs and RPMs stimulated by IL-1 and /or TNFa, but also in the PBMs of the patients with ACS.The results suggest that the expression of HGF/c-Met in monocytes/macrophages is related to the inflammatory reaction. MMPs-TIMP systems could be regulated by the interaction of HGF and c-Met. They promote the degradation of extracellular matrix and result in rupture of the plaque. The clinical evidences further indicate thatincreased serum HGF in ACS is an indicator of plaque rupture or vulnerability.