内吞相关蛋白调控AngⅡ诱导心肌肥大作用机制的研究
发布时间：2018-11-08 16:24
【摘要】： 有研究证明,受体介导的配体内吞可以降低细胞膜表面受体的数量,使受体配体复合物进入胞内溶酶体降解并发生解离,引起受体功能的下调和再循环至细胞膜表面。另外,还有学者认为内吞进入细胞内的配体受体复合物可能参与了下游信号的转导与调控,发挥其生理学及病理生理学作用。血管紧张素II(Angiotensin II,Ang II)是肾素-血管紧张素系统(Renin-angiotensin system,RAS)最主要的效应分子,具有收缩血管效应、调控醛固酮分泌等生理功能。Ang II与血管紧张素II 1型受体(Angiotensin II 1 type receptor,ATl receptor)在细胞膜表面结合,一方面激活下游信号转导途径发挥生物学作用,另一方面快速的以网格蛋白包被小泡的方式发生内吞,其中组成网格蛋白包被的主要衔接蛋白为衔接蛋白复合体2(AP2)。最近的研究表明,AngII与细胞膜表面AT1受体结合,刺激心肌细胞肥大和(或)成纤维细胞增生,是导致心肌肥厚的主要原因之一。但是,ATl受体介导的AngⅡ内吞是否也参与了心肌肥厚的形成尚需进一步地研究。本实验利用流式细胞术、激光共聚焦显微镜、RNAi、RT-PCR及Western-blot等技术,研究发现AngII可以引起H9C2细胞体积增加;p38的磷酸化形式增多,NF-κB(p65)入核增多和氯离子通道蛋白ClC-2表达增加;同时使细胞进入S期的比例增加,G1期的比例降低,提示细胞DNA和蛋白合成增加。应用内吞特异性抑制剂PAO可以抑制上述细胞体积和信号途径的改变,与应用AT1受体拮抗剂(ARB)candesartan的作用一致,即PAO与Candesartan都可抑制AngII的促细胞肥大增生作用。初步证明AngII在细胞膜上与AT1受体结合后,在激活下游心肌肥大相关信号因子的同时,发生快速的受体内吞,这种配体介导的受体内吞在进入细胞内可能依然发挥着病理生理学作用。本实验又通过RNAi技术敲除AP2,抑制网格蛋白介导的内吞,发现可以抑制AT1受体介导的AngII内吞,并影响细胞体积,细胞周期及相关信号蛋白的改变,但对ClC-2表达无明显影响。因此我们得出初步结论,ATl受体介导的AngII内吞,不但使配体受体复合物进入细胞内,发生降解和受体配体的解离,及受体的再循环,而且内吞入胞内的受体在细胞内继续发挥其生物学功能,持续激活下游信号,通过影响细胞周期的改变,引起细胞的肥大增生。但其具体作用机制还需要进一步研究探讨。
[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，
本文编号：2319030
[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，
本文编号：2319030
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