【摘要】： 有研究證明,受體介導(dǎo)的配體內(nèi)吞可以降低細(xì)胞膜表面受體的數(shù)量,使受體配體復(fù)合物進(jìn)入胞內(nèi)溶酶體降解并發(fā)生解離,引起受體功能的下調(diào)和再循環(huán)至細(xì)胞膜表面。另外,還有學(xué)者認(rèn)為內(nèi)吞進(jìn)入細(xì)胞內(nèi)的配體受體復(fù)合物可能參與了下游信號(hào)的轉(zhuǎn)導(dǎo)與調(diào)控,發(fā)揮其生理學(xué)及病理生理學(xué)作用。血管緊張素II(Angiotensin II,Ang II)是腎素-血管緊張素系統(tǒng)(Renin-angiotensin system,RAS)最主要的效應(yīng)分子,具有收縮血管效應(yīng)、調(diào)控醛固酮分泌等生理功能。Ang II與血管緊張素II 1型受體(Angiotensin II 1 type receptor,ATl receptor)在細(xì)胞膜表面結(jié)合,一方面激活下游信號(hào)轉(zhuǎn)導(dǎo)途徑發(fā)揮生物學(xué)作用,另一方面快速的以網(wǎng)格蛋白包被小泡的方式發(fā)生內(nèi)吞,其中組成網(wǎng)格蛋白包被的主要銜接蛋白為銜接蛋白復(fù)合體2(AP2)。最近的研究表明,AngII與細(xì)胞膜表面AT1受體結(jié)合,刺激心肌細(xì)胞肥大和(或)成纖維細(xì)胞增生,是導(dǎo)致心肌肥厚的主要原因之一。但是,ATl受體介導(dǎo)的AngⅡ內(nèi)吞是否也參與了心肌肥厚的形成尚需進(jìn)一步地研究。本實(shí)驗(yàn)利用流式細(xì)胞術(shù)、激光共聚焦顯微鏡、RNAi、RT-PCR及Western-blot等技術(shù),研究發(fā)現(xiàn)AngII可以引起H9C2細(xì)胞體積增加;p38的磷酸化形式增多,NF-κB(p65)入核增多和氯離子通道蛋白ClC-2表達(dá)增加;同時(shí)使細(xì)胞進(jìn)入S期的比例增加,G1期的比例降低,提示細(xì)胞DNA和蛋白合成增加。應(yīng)用內(nèi)吞特異性抑制劑PAO可以抑制上述細(xì)胞體積和信號(hào)途徑的改變,與應(yīng)用AT1受體拮抗劑(ARB)candesartan的作用一致,即PAO與Candesartan都可抑制AngII的促細(xì)胞肥大增生作用。初步證明AngII在細(xì)胞膜上與AT1受體結(jié)合后,在激活下游心肌肥大相關(guān)信號(hào)因子的同時(shí),發(fā)生快速的受體內(nèi)吞,這種配體介導(dǎo)的受體內(nèi)吞在進(jìn)入細(xì)胞內(nèi)可能依然發(fā)揮著病理生理學(xué)作用。本實(shí)驗(yàn)又通過(guò)RNAi技術(shù)敲除AP2,抑制網(wǎng)格蛋白介導(dǎo)的內(nèi)吞,發(fā)現(xiàn)可以抑制AT1受體介導(dǎo)的AngII內(nèi)吞,并影響細(xì)胞體積,細(xì)胞周期及相關(guān)信號(hào)蛋白的改變,但對(duì)ClC-2表達(dá)無(wú)明顯影響。因此我們得出初步結(jié)論,ATl受體介導(dǎo)的AngII內(nèi)吞,不但使配體受體復(fù)合物進(jìn)入細(xì)胞內(nèi),發(fā)生降解和受體配體的解離,及受體的再循環(huán),而且內(nèi)吞入胞內(nèi)的受體在細(xì)胞內(nèi)繼續(xù)發(fā)揮其生物學(xué)功能,持續(xù)激活下游信號(hào),通過(guò)影響細(xì)胞周期的改變,引起細(xì)胞的肥大增生。但其具體作用機(jī)制還需要進(jìn)一步研究探討。
[Abstract]:It has been shown that ligand endocytosis mediated by receptor can reduce the number of receptors on the surface of cell membrane, make the receptor ligand complex enter into the cell lysosome degradation and dissociate, and cause the down-regulation and recirculation of receptor function to the surface of cell membrane. In addition, some scholars believe that the ligand receptor complex of endocytosis may participate in downstream signal transduction and regulation, and play a physiological and pathophysiological role. Angiotensin (II (Angiotensin II,Ang II) is the most important effector molecule of renin-angiotensin system (Renin-angiotensin system,RAS) and has vasoconstriction effect. Regulating the secretion of aldosterone and other physiological functions of. Ang II and angiotensin II type 1 receptor (Angiotensin II 1 type receptor,ATl receptor binding on the surface of cell membrane, on the one hand activation of downstream signal transduction pathway play a biological role. On the other hand, endocytosis occurs rapidly in the form of griddle protein coated vesicles, in which the main binding protein composed of gridding protein envelope is junction protein complex 2 (AP2). Recent studies have shown that AngII binds to AT1 receptors on cell membrane and stimulates cardiac hypertrophy and / or fibroblast proliferation, which is one of the main causes of myocardial hypertrophy. However, whether Ang 鈪，

本文編號(hào)：2319030