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Effects of Aralosides to CD40L Expression during Rat Myocardial Ischemia Reperfusion

Author: CuiXianJun
Tutor: LuWeiXing
School: Beijing University of Traditional Chinese Medicine
Course: Traditional Chinese Medicine Department of Cardiology
Keywords: Aralosides replenishing qi and activating blood CD40/CD40L myocardial cell ischemia reperfusion injury inflammatory
CLC: R285.5
Type: PhD thesis
Year: 2008
Downloads: 127
Quote: 0
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Abstract


Back Ground and Objective:In the past decade, the CD40-CD40L system has attracted increased interest in the medical community as a major player in a wide array of chronic inflammatory and autoimmune diseases, among them atherosclerosis. Acute coronary syndromes (ACS) are always initiated by disrupted or eroded atherosclerotic plaque and platelets activation. CD40L is gaining much attention for its role in the initiation and progression of atherosclerosis. Apart from surface-expressed CD40L, it can be cleaved into plasma and become soluble CD40L(sCD40L).Elevated levels of sCD40L have been reported in patients with both stable or unstable angina (UA), acute myocardial infarction (AMI). Studies on the cellular distribution of CD40L indicate that more than 95% of the circulating CD40L derives from platelets.CD40L, cryptic in unstimulated platelets, is expressed on the surface of platelets within seconds of platelet activation and then cleaved to generate a soluble, trimeric fragment, sCD40L. The peculiarity of CD40L as an inflammatory mediator derived from platelets expands the functional repertoire of platelets from players of haemostasis and thrombosis to powerful amplifiers of inflammation by promoting the release of cytokines and chemokines, cell activation and cell-cell interactions. The most important transcription factor that is activated by CD40 signaling is nuclear factor kappa B (NF-κB). Nuclear factor kappa B translocation into the nucleus results in the expression of pathways of inflammation, thrombosis. It has been reported that CD40/CD40L signaling plays a major role in inducing the proinflammatory and prothrombogenic phenotype that is assumed by the cerebral microvasculature after transient, focal, cerebral ischemia. This signaling pathway also makes a significant contribution to the endothelial barrier dysfunction and tissue necrosis that accompany brain ischemia reperfusion (I/R). Aralia elata possesses function of benefiting vital energy and promoting blood flow. And its principle active ingredient aralosides has been documented the effectiveness of anti-inflammatory, abatement injury caused by free radical and myocardial ischemia. So far, there is no document about the relationship between CD40/CD40L and myocardial ischemia reperfusion injury. The study was performed by using myocardial I/R model to investigate the role of CD40/CD40L in the myocardial I/R injury.Methods and Results:PartΙ:Establishing myocardial I/R model of rat to explore characteristic pathological alteration of myocardium tissue during the procedure of I/R injury. Male Wistar rats were utilized to establish myocardial I/R model, by anterior descending branch ligated and loosed. Ligation duration is respectively 15、30、45 minutes to create ischemia model. After 45 minutes ligation, loose duration is respectively 5、15、30 minutes to make reperfusion model. Sham operation groups of similar ischemia and reperfusion duration and a normal group were set up to compare. HE stain paraffin sections were applied to histological anatomy observation, by comparison with sham operation group and normal group, pathologic alterations of myocardial I/R injury were founded. The pathologic characteristic alteration of heart muscle fiber is wave-like change, closely related to ischemia and reperfusion duration. Blood constituent effusion is more obviously in reperfusion tissue. This lay a foundation to explore the location of CD40 and CD40L.PartΠ:To elucidate relationship of CD40 and CD40L between myocardial I/R injury. CD40Lwas identified at endothelial cell surface of endocardium and vascular in diseased region by Immunohistochemical staining. CD40L, expressed on endocardium surface, is one of mechanism of platelet activation during myocardial ischemia. The relationship between the quantity of CD40L and IR was also detected by image analysis. And the maximum was at the point of reperfusion 5 minutes, but compared to others, there was no significant difference among them(P>0.05).PartⅢ:To investigate effects of aralosides and tirofiban to the quantity of CD40Lexpression on endocardium during myocardial ischemia reperfusion. As a result, both aralosides and tirofiban reduced the quantity of CD40L expression significantly, however, tirofiban did well than aralosides.Conclusion:There were characteristic pathologic alterations during early myocardial ischemia reperfusion. CD40L was definitely located on endothelial surface in diseased region and could make platelets activated. Both aralosides and tirofiban could effectively reduce the quantity of CD40Lexpresion on endocardium. This was a new mechanism of their pharmacologic action and as a proof for them to be applied to ACS.

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