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辛伐他丁減少Connexin43表達(dá)和兔粥樣硬化斑塊形成
作者:李建軍,林宏,李柱一,李宏增【關(guān)鍵詞】 動(dòng)脈粥樣硬化
Simvastatin reduces Connexin43 expression and inhibits rabbit atherosclerotic lesion formation
【Abstract】 AIM: To demonstrate that simvastatin can influence atherosclerotic plaque formation and stability by decreasing the expression of gap junction protein connexin43 (Cx43) in atherosclerotic lesions. METHODS: The role of Cx43 in atherogenesis was examined by a pharmacological approach. The rabbit model of atherogenesis was established by a highcholesterol diet. The expression of connexin 43 and macrophages in vivo was determined by immunohistochemistry and the expression of connexin 43 in cultured smooth muscle cells was determined with Western blot. The quantity of connexin43 expression was analyzed with computer images. RESULTS: We observed that HMGCoA reductase inhibitors, or "statins", lipidlowering drugs well known for their pleiotropic antiatherogenic effects, reduced Cx43 expression in primary human vascular cells in vitro. Atheroma of rabbits orally treated with simvastatin contained fewer inflammatory cells and exhibited thicker fibrous caps than controls, which was associated with reduced Cx43 expression in lesions of statintreated rabbits. CONCLUSION: These data indicate the critical role of Cx43mediated gap junctional communication in atherosclerotic plaque formation. Reduced Cx43mediated intercellular communication leads to changes in atherogenesis. These findings show that Cx43mediated intercellular communication can be used as a new potential therapeutic target in atherogenesis.
【Keywords】 atherosclerosis; simvastatin; Connexin43
【摘要】 目的:證明辛伐他丁可以通過(guò)減少縫隙連接蛋白43(Connexin43, Cx43)的表達(dá)影響粥樣斑塊的形成及穩(wěn)定性. 方法:高脂飼料喂養(yǎng)建立粥樣硬化模型,治療組給予辛伐他丁口服,活體內(nèi)的Cx43和巨嗜細(xì)胞檢測(cè)使用免疫組織化學(xué)方法,培養(yǎng)平滑肌細(xì)胞的Cx43檢測(cè)使用免疫印記方法,Cx43的半定量使用計(jì)算機(jī)圖像處理. 結(jié)果:藥物干預(yù)的培養(yǎng)細(xì)胞和模型治療組中Cx43的表達(dá)均明顯減少,斑塊的組成中,炎癥細(xì)胞減少50%,膠原纖維平滑肌細(xì)胞含量增加. 結(jié)論: Cx43介導(dǎo)的細(xì)胞間通訊在粥樣硬化形成中起重要作用,同時(shí)辛伐他丁減少Cx43的表達(dá)可以增加斑塊的穩(wěn)定性,Cx43成為動(dòng)脈粥樣硬化治療中一個(gè)新的治療靶點(diǎn).
【關(guān)鍵詞】 動(dòng)脈粥樣硬化;辛伐他;連接蛋白43
0引言
動(dòng)脈粥樣硬化主要是一種免疫炎癥性疾病,它的病理過(guò)程是多因素參與的. 包括富含脂質(zhì)的巨嗜細(xì)胞和T淋巴細(xì)胞在血管內(nèi)皮下積聚(脂質(zhì)條紋). 由多層的泡沫細(xì)胞和增生的平滑肌細(xì)胞組成,并伴隨有細(xì)胞外基質(zhì)的沉積(粥樣斑塊). 在粥樣斑塊形成過(guò)程中的決定性因素是循環(huán)中的血液細(xì)胞和動(dòng)脈壁內(nèi)的細(xì)胞之間相互協(xié)調(diào)的作用[1,2].
縫隙連接是由許多相關(guān)的蛋白家族組成的,叫做Connexins(Cxs)[3]. 在人體中大約有20多種的Cxs,Cx43是分布最廣泛的. Cxs是機(jī)能蛋白,半衰期是1~5 h左右,在生理和病理?xiàng)l件下提供了細(xì)胞間相互影響的一種方式[4]. 細(xì)胞間通道的代表縫隙連接在多細(xì)胞有機(jī)體中通過(guò)直接的交換離子和小分子物質(zhì)提供了一種簡(jiǎn)單的同步反應(yīng)的方式[5],縫隙連接在慢性的生理過(guò)程如細(xì)胞的生長(zhǎng)發(fā)育中起到重要作用. 已經(jīng)證明在粥樣硬化形成中Cx43的表達(dá)增加,Cx43在粥樣硬化的發(fā)病過(guò)程中起著重要作用. 我們用實(shí)驗(yàn)證明,辛伐他丁可以通過(guò)減少Cx43的表達(dá)影響粥樣斑塊形成.
1材料和方法
1.1材料
兔粥樣硬化模型的建立: 3 mo齡健康新西蘭兔20只,購(gòu)自第四軍醫(yī)大學(xué)實(shí)驗(yàn)動(dòng)物中心,體質(zhì)量2~3 kg,適應(yīng)性喂養(yǎng)1 wk后記錄血脂,隨機(jī)分成兩組,每組10只,第一組給予高膽固醇飲食(每100 g飼料含有1 g膽固醇、15 g蛋黃粉,5 g豬油,其余為兔基礎(chǔ)飼料)及4 mg/(kg
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