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The Correlation between sCD40L、MMP-2、MMP-9 and the Coronary Artery Lesion and the Studys on the Effects of Rosuvastatin

Author: MengXiangYan
Tutor: GaoChangBin
School: Jilin University
Course: Internal Medicine
Keywords: acute coronary syndrome (ACS) soluble CD40L ligand (sCD40L) matrix metalloproteinase 2 (MMP-2) matrix metalloproteinase 9 (MMP-9) rosuvastatin
CLC: R541.4
Type: PhD thesis
Year: 2011
Downloads: 150
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Atherosclerosis (AS) is the most common cause of ischemic heart disease. Among it, acute coronary syndrome (ACS) is one manifestation of coronary heart disease (CHD) whose pathogenesis mainly are the rupturing of atherosclerotic plague, vasoconstriction or thrombosis, which leads to sudden reduction of coronary blood flow. The important role of Inflammatory reaction in the occurrence of atherosclerosis, development process and cause the instability of the atherosclerotic plaques has already get the attention of scholars both at home and abroad more and more. Reduce the level of inflammation factor with ACS can reduce the incidence of coronary events。Metalloproteinase (MMP), cytokines, adhesion molecules and various enzymes involved in the inflammatory process.The CD40-CD40L is a pair of transmembrane glycoprotein with homology to tumor necrosis factor receptor (TNFR) family. The interaction of CD40 with CD40L plays an important role of signal transduction pathway in the inflammatory process. widely express in the immune cell surface of atherosclerosis, play an important role in the immune process of chronic inflammation in the formation and development of atherosclerosis.Soluble CD40L (sCD40L) is the CD40L ligand,has strong biological activity, can interact with CD40 which on the surface of thevascular smooth muscle cells,and endothelial cells etc, through the Induction of MMPs gene expression, play a key role in the formation and stability of plaques, and c losely related to the prognosis of ACS.MMPs is endogenous protease family of zinc ion dependent, and necessary in the process of extracellular matrix (ECM) degradation, plays an important role in the process of ECM reconstruction In ACS lesions. It’s an important cell signal transduction pathways in the reaction process of inflammation, and a main cell components that participate in the inflammation adjustment of atherosclerotic plaque. MMP-2 and MMP-9 are the important enzymes which bring about plaques unstable.One of the purposes of this study is the using AS rat model to investigate the role of peripheral blood CD40、CD40L and MMP-2、MMP-9 in the formation of atherosclerosis and the relationship between each other.CD40-CD40L、MMP-2 and MMP-9 play an important role in the formation and development of atherosclerosis, but the relationship with the lesions of coronary artial, and if can be the biochemical indicators to prognosis unstable plaque, preliminary assess the severity and scope of coronary lesions, provide basis for clinical, all those have been more concern at present.The second purpose of this study is detecting the serum level of sCD40L MMP-2 and MMP-9 in subtypes of ACS patient, comparing with normal group, combined with the results of coronary angiography, analyzing the relationship between level of sCD40L, MMP-2 and MMP-9 and coronary lesions. Discussing the possibility of sCD40L, MMP-2, MMP-9 levels in serum serving as biochemistry indicators in estimating the types and severities, evaluating the unstability of coronary atherosclerosis plaque, assessing the risk of coronary heart disease, and forecasting the occurrence of ACS。Rosuvastatin is a synthesis HMG-CoA of drug, that has highly liver selectivity, relative hydrophilic, except has lowering lipid、adjusting endothelial function etc. multiple effections, mainly by reducing the CD40 expression in the plaque, antagonisting the inflammatory reaction of coronary artery inner membrance, play a key role in the stable plaques, in a certain extent, improve the prognosis of patients, and has become the first-line drug in prevention atherosclerosis and complications.But now there is little study in statin playing anti-inflammatory effects early and about the concentration-response relationship.The third purpose of this study is prescribing ACS patients with different doses of rosuvastatin in order to observe its effect on sCD40L, MMP-2 and MMP-9 levels, investigate the involvement of statins in the treatment of inflammation which will provide a theoretical basis to clinical application of statins.Materials and MethodsAnimal experiment:A typical AS model was made of the high-lipid-diet rat. AS group (n=7) and normal control (N group, n=11) feed with the normal diet were under observation. The CD40 and CD40L of rat peripheral blood were detected by flow cytometry. Immunohistochemistry was employed to detect the local expression of CD40 and CD40L on aortic arch. The matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) of peripheral blood were measured by Gelatin-PAGE (Substrates glue electrophoresis) method, analyzing the OD value of MMP-2 and MMP-9 in each group. Do the correlation analysis between CD40、CD40L and MMP-2、MMP-9.Clinical Trials:The patients diagnosed as coronary heart disease were enrolled and divided into three groups:stable angina group (SAP group), unstable angina group (UAP group), acute myocardial infarction group (AMI group). Patients with normal coronary angiography were enrolled as control (control group). The concentrations of sCD40L, MMP-2, MMP-9 in plasma were measured by ELISA. The correlation between the level of sCD40L, MMP-2, MMP-9 and the coronary artery lesion was analyzed (confirmed by coronary angiography). Do the correlation analysis between sCD40L and MMP-2、MMP-9. AMI group and UAP group treated with percutaneous coronary intervention (PCI) were divided into 10mg rosuvastatin group and 40mg rosuvastatin group,observed the pre-operrative and post-operative level trends of sCD40L, MMP-2, MMP-9,the level of those patients were observed in pre-operation, post-operation,1 day,3 days,5 days,7 days,14 days with different doses rosuvastatin.Statistics:Numerical data are expressed as mean±standard deviation (M±SD). SPSS 10.0 was used to analyze the data. Anova were used to compare among multiple groups, and q test for between groups. t test for comparing means of two groups. p<0.05 was considering as statistical difference.ResultsAnimal experiment:By flow cytometry, the mean fluorescence intensity (MFI) of CD40 and CD40L in AS group were significantly higher than N group (P<0.05). CD40 and CD40L were strongly expressed in AS group, especially at the position of AS plaque; CD40 and CD40L were weakly expressed in N group. By Zymography method, the OD value of MMP-2 and MMP-9 in AS group were significantly higher than N group (P<0.05). These results indicates the abnormal expression of CD40, CD40L and MMP-2, MMP-9 is closely correlated with the formation of AS.Clinical Trials:(1).The serum levels of sCD40L and MMP-9 in AMI group were significantly higher than that UAP group (P<0.01). MMP-2 level in AMI group was higher than UAP group (P>0.05). The serum levels of sCD40L, MMP-9 and MMP-2 in AMI group were significantly higher than SAP and control group (P<0.05), they were comparable in SAP and control group.(2).In AMI and UAP group, sCD40L, MMP-2 and MMP-9 level in the subgroup with type C lesion are remarkably higher than that in subgroup with type B and A lesion (P<0.01), and they are higher in type B lesion subgroup than type A lesion subgroup (P<0.05).(3).In AMI and UAP group, sCD40L, MMP-2 and MMP-9 level were higher in the subgroup with three vessels lesion than that in the subgroup with two vessels and single vessel lesion (P<0.01), and they were higher in two vessels subgroup than single vessel group (P<0.05).(4). The concentration of sCD40L was positively related with MMP-2 and MMP-9 concentration.(5). The level of sCD40L, MMP-2 and MMP-9 have the same trends roughly, sCD40L, MMP-2, MMP-9 level increased remarkably one day after PCI (VS pre-PCI, P<0.05), and gradually decreased after three days, then reached the level of pre-PCI from 5-7 days after PCI. The level of sCD40L, MMP-2, MMP-9 decreased significantly 28 days after PCI than pre-PCI (P<0.05). However, one day after PCI, in 40mg rosuvastatin treated group, the absolute increased value of sCD40L, MMP-2 and MMP-9 level were smaller than that in 10mg rosuvastatin treated group.Conclusion(1).The increasing of sCD40L, MMP-2, MMP-9 expression in rats are mostly related to the AS, so sCD40L and MMP-9 may be related to the occurrence of acute coronary syndrome.(2).sCD40L, MMP-2, MMP-9 levels in serum can serve as inflammatory indicators for the stability of coronary atherosclerosis plaque. sCD40L, MMP-9 level combining with coronary angiography are useful to stratify the risk levels of coronary heart disease and the severity of coronary artery lesion, it has important significance on evaluation severity of coronary artery disease.(3).There is a dose-dependent effect between rosuvastatin and inhibition of inflammatory cytokines. High dose rosuvastatin significantly early decreased level of inflammatory factors in serum, which may reduce the degradation of matrix elements of atherosclerotic plaque and inflammation.

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CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Heart disease > Coronary arteries ( atherosclerosis ),heart disease (CHD)
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