A Study On The Relationship Between Expression Of Vascular Endothelial Growth Factor And Atherosclerosis And The Effects Of Simvastatin

It is well known that rupture of unstable atherosclerotic plaque with subsequent thrombosis is probably one of the most important mechanisms of the sudden onset of acute coronary syndrome(ACS).Angiogenesis as well as adhesion is the manifestation of inflammatory reaction in the plaques,which may reduce the stability of plaques and induce rupture of plaques and thrombosis.Vascular endothelial growth factor(VEGF) is a pleiotropic factor mainly derived from vascular endothelial cell,so far it is the only specific mitogen of vascular endothelial cell.Most of the biological functions of VEGF is encoded by his specific high affinity receptor fetal liver kinase-l(Flk-l).VEGF improved angiogenesis directly,as well as involved in inflammatory process in plaques,so we speculated that VEGF/Flk-1 play an important role in the pathogenesis and development of atherosclerosis.Cellular adhesion molecule(CAM) is a kind of glucoprotein expressed on the membrane surface of various cells,which mediate the conjunction and adhesion of cells and extracellular matrix.Vascular cellular adhesion molecule-1(VCAM-1) and intercellular adhesion molecule-1 (1CAM-1) are members of CAM.Adhesion is one of the initiating factors of inflammatory process in plaques and is relative to the pathogenesis and development of atherosclerosis.The aims of this study are following:(l)to examine the expression levels of VEGF and VCAM-1 in atherosclerotic plaque or in circulation,(2)to examine the expression levels of VEGF/Flk-1,VCAM-1 and ICAM-1 in human umbilical vascular endothelial cell(HUVEC) after stimulated by inflammatory cytokines,(3)to examine the effects of simvastatin or Tongxinluo on process(l) and process(2),and to explore anew way to stabilize vulnerable plaques so as to prevent the patients from the onset of ACS.The rabbit aortic atherosclerotic model was developed by high cholesterol feeding.The protein levels of VEGF and VCAM-1 in atherosclerotic plaques were studied by means of immunohistochemistry and Western Blot.The mRNA levels of VEGF were studied by means of reverse transcription polymerase chain reaction(RT-PCR).We found that simvastatin and Tongxinluo decreased the levels of VEGF and VCAM-1 in atherosclerotic plaques,and decreased the concentrations of oxidized low density lipoprotein and lactate dehydrogenase.The effects of tumor necrosis factor- (TNF- ) and interleukin-l(3(IL-l(3) on the protein levels of VEGF,Flk-l,VCAM-1 and ICAM-1 in HUVEC were studied by means of immunocytochemistry and Western Blot.The mRNA levels of VEGF,Flk-l,VCAM-1 and ICAM-1 were studied by means of RT-PCR.We found that TNF-a and IL-lp increase the expression levels of VEGF,Flk-l,VCAM-1 and ICAM-1 in endothelial cell.The effects of TNF- a and IL-1J3 were inhibited either by Simvastatin or by SU5416,a specific inhibitor of Flk-1.The serial changes of VEGF and soluble VCAM-l(sVCAM-l) levels in serum were determined by enzyme-linked immunosorbent assay in the patients with ACS.The serum levels of VEGF and sVCAM-1 in ACS group were significantly higher than those in stable angina pectoris group and control group within 24h after the onset of chest pain.The serum levels of VEGF and sVCAM-1 in the patients with ACS decreased significantly after 2 weeks treatment of simvastatin or Tongxinluo on the basis of routine treatment,while no significant changes of VEGF and sVCAM-1 were examined in patients with routine treatment only.The results of experimental study suggest that the expressions of VEGF/Flk-1 and CAM are related to the inflammatory reaction,which reduced the stability of plaques.The clinical evidences further indicated that the serum levels of VEGF and sVCAM-1 in ACS are indicators of the stability of plaques.Simvastatin and Tongxinluo decreased the expressions of VEGF and VCAM-1 in plaque or in circulation.Simvastatin decreased the expressions of VEGF/Flk-1 and CAM inHUVEC stimulated by inflammatory cytokines.lt suggests that simvastatin and Tongxinluo play important roles in stabilizing vulnerable plaque.