神经调节蛋白-1β及其受体信号系统对心肌细胞的调控作用及其机制研究
发布时间：2018-07-31 11:06
【摘要】：寻求新的保护因子或新的治疗策略对心肌细胞(cardiac muscle cell,CM)的保护作用及其机制对于心脏疾病的治疗和改善心功能具有重要的意义。虽然对心肌细胞肥大和心室重构的研究取得了许多重大的突破性进展,但这众多的研究成果大多是基于心肌细胞或心室结构本身而开展的,而对心脏神经调控机制对心肌细胞结构和功能的影响尚有待于从更广和更深的层次开展研究。神经调节蛋白-1β(neuregulin-1β,NRG-1β)可通过激活其酪氨酸激酶受体ErbB2和ErbB4而对神经元发挥多种调控作用,NRG-1β很可能具备对心脏神经发挥特有的调控作用的潜能,到目前为止,还没有发现NRG-1β通过调控心脏神经而对心肌发挥调控作用的报道。有趣的是,NRG-1β还可对心肌细胞直接发挥重要的调控功能。鉴于心脏神经和心肌细胞均为NRG-1β直接调控的靶组织,这将使NRG-1β对心功能的调节作用机制更为复杂。本课题将基于以上研究背景开展如下一系列实验研究:首先,研究NRG-1β对培养的新生大鼠心肌细胞的ErbB2和ErbB4受体及其下游的磷酸肌醇-3-激酶(phosphoinositide-3 kinase,PI3K)/蛋白激酶B(protein kinase B,PKB,Akt)和细胞外信号调节激酶 1/2(extracellular signal-regulated kinase 1/2,ERK1/2)的表达及其激活的影响作用;其次,研究NRG-1β及其相关的信号通路对心肌细胞重要的形态指标和功能指标的影响作用;最终,利用具有选择性交感神经支配的心肌细胞,研究NRG-1β及其相关的信号通路对神经和心肌的双重调控作用。通过以上系列研究,以便进一步阐明NRG-1β直接调节心肌细胞或通过调节其神经支配而调节心肌细胞的作用及其机制。从而提出不仅通过NRG-1β及其受体信号的活性而直接增强心肌细胞再生能力或功能,而且还可通过NRG-1β及其受体信号系统介导的心脏神经调控作用而进一步增强其对心肌细胞结构和功能的调控作用的新的治疗策略。第一部分神经调节蛋白-1β在心肌细胞激活其受体及其下游信号通路的实验研究NRG-1β对心肌细胞ErbB2和ErbB4受体及其下游的PI3K/Akt和ERK1/2的激活是其发挥生物学效应的重要途径。为了研究NRG-1β对心肌细胞ErbB2和ErbB4受体及其下游的信号分子Akt和ERK1/2表达及其激活的影响作用,本课题利用培养的新生大鼠心肌细胞观察了 NRG-1β快速孵育和持续孵育对这些分子表达和激活的影响作用程度。结果显示,NRG-1β急性孵育不会对心肌细胞表面积产生影响,而NRG-1β持续孵育,则可增加心肌细胞的表面积,有利于心肌细胞的生长发育;NRG-1β急性孵育虽然不能促进其受体ErbB2和ErbB4及其下游信号分子Akt和ERK1/2的表达,但可显著提高其磷酸化水平,表明NRG-1β急性孵育可激活其受体及其相关的下游细胞信号转导通路;NRG-1β持续孵育不仅能促进其受体ErbB2和ErbB4及其下游信号分子Akt和ERK1/2的表达,而且还使其磷酸化水平显著上升,从而改善心肌细胞的生长状态;NRG-1β的促心肌细胞生长效应可被PI3K抑制剂LY294002或ERK1/2抑制剂PD98059所阻断,而不能阻断NRG-1β的诱导其受体ErbB2和ErbB4表达和磷酸化的效应。以上结果表明,NRG-1β急性孵育和NRG-1β持续孵育对心肌细胞具有不同的生物学效应。NRG-1β急性孵育和NRG-1β持续孵育对其受体ErbB2和ErbB4及其下游信号分子Akt和ERK1/2表达和激活的不同生物学效应揭示了将来利用NRG-1β治疗相应的心脏疾患所可能采取的不同治疗策略。第二部分神经调节蛋白-1β改善心肌细胞结构和功能指标的作用参与粗肌丝构成的肌球蛋白重链(myosin heavy chain,MHC)、能够激活调节性肌球蛋白轻链(myosin regulatory light chain,rMLC)的心肌特异的肌球蛋白轻链激酶(cardiac-specific myosin light-chain kinase,cMLCK)是调节肌节组装的重要因子,心肌细胞的主要门控通道L-型钙通道(L-type calcium channel,LTCC,Cav1.2)是Ca2+进入心肌细胞的主要通道,肌质网钙离子三磷酸腺苷酶或肌质网钙离子泵(sarco(endo)plasmic reticulum Ca2+ ATPases or sarco(endo)plasmic reticulum-Ca2+ pump,SERCA2a)通过将胞质内 Ca2+的转运至肌质网(sarcoplasmic reticulum,SR)内,从而调节收缩和舒张循环的协调性。以上指标是影响心肌细胞结构和功能的关键因素,为了检测NRG-1β对这些指标的影响作用及其相关机制,本课题利用培养的新生大鼠心肌细胞,研究了 NRG-1β及其相关的信号通路对心肌细胞的这些重要形态指标和功能指标的影响作用,并深入分析了 NRG-1β改善心肌细胞内在组分的潜能。结果显示,NRG-1β可分别促进培养的心肌细胞代表性结构指标MHC、对心肌细胞内的关键激酶cMLCK、代表性功能指标L-型钙通道和SERCA2a的表达,P13K抑制剂LY294002或ERK1/2抑制剂PD98059可抑制NRG-1β引起的促心肌细胞MHC、cMLCK、L-型钙通道和SERCA2a表达上调的作用。这些结果表明,NRG-1β可有效促进对心肌细胞收缩的基本结构分子和功能分子的表达,从而改善心肌细胞的内在组分构成,并由此而提高心肌细胞功能的潜在能力,这是NRG-1β将来有可能成为改善心功能的有效治疗分子的重要实验依据。第三部分神经调节蛋白-1β增强心肌细胞去甲腺素能命运的潜能心肌细胞的去甲肾上腺素能命运是保证和维持心肌细胞功能的前提,在此基础上,心肌细胞的功能调控还有赖于正常交感神经的支配。心肌细胞β-肾上腺素能受体(β-adrenergic receptor,β-AR)的表达是心肌细胞的去甲肾上腺素能命运的重要体现,β-AR的激活是交感神经支配信号传递的必由途经。本课题将根据NRG-1β及其相关的信号通路对神经和心肌的双重调控作用,建立器官型的颈上神经节(superior cervical ganglion,SCG)组织块和分散心肌细胞的联合培养体系,研究有或没有交感神经支配的培养的心肌细胞,再附加NRG-1β孵育的条件下,心肌细胞去甲肾上腺素能命运潜能的变化。结果显示,NRG-1β孵育可使心肌细胞β1-AR和β2-AR的表达水平上调,而选择性交感神经支配使心肌细胞β1-AR和β2-AR表达水平上调的效应更加明显,NRG-1β孵育可进一步增强交感神经支配信号对心肌细胞β1-AR和β2-AR表达水平上调的促进效应;在心肌细胞与交感神经元联合培养的过程中,应用NRG-1β孵育能够通过增加交感神经元突起的数目增强交感神经信号对心肌细胞支配的效能;PI3K抑制剂LY294002或ERK1/2抑制剂PD98059可抑制NRG-1β引起的促心肌细胞β1-AR和β2-AR表达上调作用和促神经元突起生长的效应。这些结果表明,NRG-1β具有进一步增强交感神经支配信号的促心肌细胞去甲肾上腺素能命运的效应,这一效应是通过PI3K/Akt和ERK1/2细胞信号转导通路介导的。本课题的研究结果对于以NRG-1β及其受体信号系统为主导的具有针对性的治疗策略的制定提供了具有指导意义的理论基础和具有参考价值的实验依据。
[Abstract]:The protective effect of new protective factors or new therapeutic strategies on cardiac muscle cell (CM) and its mechanism are of great significance for the treatment of heart disease and the improvement of cardiac function. Although many major breakthroughs have been made in the study of cardiac myocyte hypertrophy and ventricular remodeling, many research achievements have been made. Many of them are based on cardiac myocytes or ventricular structure itself, and the effect of the cardiac nerve regulation mechanism on the structure and function of cardiac myocytes remains to be studied from a broader and deeper level. The neuroregulatory protein -1 beta (neuregulin-1 beta, NRG-1 beta) can play a role in neurons by activating its tyrosine kinase receptor ErbB2 and ErbB4. A variety of regulatory functions, NRG-1 beta is likely to have the potential to play a unique regulatory role in the heart nerve. Up to now, there has been no discovery of the regulation of the NRG-1 beta by regulating the heart nerve. It is interesting that NRG-1 beta can also play an important regulatory function on cardiac myocytes. All the cells are the target tissues directly regulated by NRG-1 beta, which will make the regulatory mechanism of NRG-1 beta more complex. This topic will be based on a series of experimental studies based on the above research background. First, the ErbB2 and ErbB4 receptors of NRG-1 beta cultured neonatal rat cardiomyocytes and their downstream inositol -3- kinase (phosphoi) are studied. Nositide-3 kinase, PI3K) / protein kinase B (protein kinase B, PKB, Akt) and the expression of extracellular signal regulated kinase 1/2 (extracellular signal-regulated) and its effect on activation; secondly, the effect of beta and its related signal pathways on the important morphological and functional indexes of cardiac myocytes; Finally, using the cardiomyocytes with selective sympathetic innervation, the dual regulatory role of NRG-1 beta and its related signaling pathway on the nerve and myocardium is studied. Through the above series of studies, the role and mechanism of NRG-1 beta regulating cardiac myocytes directly or regulating the innervation of the cardiac myocytes by regulating their innervation are further elucidated. A new therapeutic strategy is proposed to enhance the ability or function of cardiac myocyte regeneration not only through the activity of NRG-1 beta and its receptor signal, but also through the regulatory role of the cardiac nerve in the NRG-1 beta and its receptor signaling system. Experimental study of white -1 beta activation of its receptor and its downstream signaling pathway in cardiac myocytes: NRG-1 beta activation of ErbB2 and ErbB4 receptors and its downstream PI3K/Akt and ERK1/2 is an important pathway for its biological effects. In order to study the expression of NRG-1 beta on ErbB2 and ErbB4 receptors and the downstream signaling molecules Akt and ERK1/2 expression of NRG-1 beta The effect of NRG-1 beta incubation and continuous incubation on the expression and activation of these molecules was observed by the cultured neonatal rat cardiomyocytes. The results showed that the acute incubation of NRG-1 beta did not affect the surface area of cardiac myocytes, while NRG-1 beta incubation could increase the myocardial cells. The surface area is beneficial to the growth and development of cardiac myocytes; the acute incubation of NRG-1 beta can not promote the expression of its receptor ErbB2 and ErbB4 and their downstream signal molecules Akt and ERK1/2, but can significantly increase their phosphorylation level. It indicates that the acute incubation of NRG-1 beta can activate its receptor and its related downstream cell signal transduction pathway; NRG-1 beta incubates continuously. It can not only promote the expression of its receptor ErbB2 and ErbB4 and their downstream signal molecules Akt and ERK1/2, but also increase their phosphorylation level significantly, thus improving the growth state of cardiac myocytes; the growth effect of NRG-1 beta myocytes can be blocked by PI3K inhibitor LY294002 or ERK1/2 inhibitor PD98059, but can not block the induction of NRG-1 beta. The effects of receptor ErbB2 and ErbB4 expression and phosphorylation show that NRG-1 beta acute incubation and NRG-1 beta incubation have different biological effects on cardiac myocytes with different biological effects of.NRG-1 beta incubation and NRG-1 beta incubation on the different biological effects of ErbB2 and ErbB4 and its downstream signal molecules Akt and ERK1 /2 expression and activation. The different treatment strategies may be taken in the future using NRG-1 beta for the treatment of corresponding cardiac disorders. The role of the second part of the neuromodulation protein -1 beta to improve the structure and function of cardiac myocytes is involved in the myosin heavy chain (myosin heavy chain, MHC), which can stimulate the light chain (myosin regulatory lig) of the myosin (myosin regulatory lig). The myocardial specific myosin light chain kinase (cardiac-specific myosin light-chain kinase, cMLCK) of HT chain, rMLC is an important factor regulating the assembly of myosine, the main gated channel of cardiac myocytes is the L- type calcium channel (L-type calcium channel) is the main channel to enter the cardiac myocytes, and the calcium ion three phosphate gland of the sarcoplasmic reticulum Sarco (Endo) plasmic reticulum Ca2+ ATPases or sarco (Endo) plasmic reticulum-Ca2+ pump, which regulates the coordination of contractile and diastolic circulation by transferring the cytoplasm to the sarcoplasmic reticulum. The above index is the key to the structure and function of the cardiac myocytes. Key factors, in order to detect the effect of NRG-1 beta on these indexes and their related mechanisms, we used the cultured neonatal rat cardiomyocytes to study the effects of NRG-1 beta and related signal pathways on these important morphological and functional indexes of cardiac myocytes, and the improvement of NRG-1 beta to improve the internal group of cardiac myocytes. The results showed that NRG-1 beta could promote the representative structural index MHC of cultured cardiac myocytes, the key kinase cMLCK in the cardiac myocytes, the expression of L- type calcium channel and SERCA2a, the P13K inhibitor LY294002 or ERK1/2 inhibitor PD98059 could inhibit the MHC, cMLCK, and calcium channel induced by NRG-1 beta. These results suggest that NRG-1 beta can effectively promote the expression of the basic structural molecules and functional molecules of cardiac myocyte contraction, thus improving the intrinsic composition of cardiac myocytes and thereby enhancing the potential ability of cardiac myocyte function, which is an effective treatment for NRG-1 beta in the future to improve cardiac function. The third part of the neuromodulation protein -1 beta enhances the fate of noradrenalin in cardiac myocytes, the fate of noradrenalin in cardiac myocytes is the prerequisite to guarantee and maintain the function of cardiac myocytes. On this basis, the function regulation of cardiac myocytes depends on the control of normal sympathetic nerve. The expression of adrenergic receptor (beta -adrenergic receptor, beta -AR) is an important manifestation of the fate of noradrenalin in cardiac myocytes. The activation of beta -AR is a must by the transmission of sympathetic innervation signal. This subject will establish an organotypic neck based on the dual regulatory effect of NRG-1 beta and its related signal pathways on the nerve and myocardium. A joint culture system of the superior cervical ganglion (SCG) tissue and scattered myocardial cells to study the cultured cardiac myocytes with or without sympathetic innervation, and then add NRG-1 beta incubation to change the fate potential of norepinephrine in the cardiomyocytes. The results show that NRG-1 beta incubation can make myocardial cells beta 1-AR. And the expression level of beta 2-AR was up-regulated, and the effect of selective sympathetic innervation on the up regulation of beta 1-AR and beta 2-AR expression was more obvious. NRG-1 beta incubation could further enhance the promotion effect of sympathetic innervation signal on the up regulation of the expression level of beta and beta 2-AR in cardiac myocytes, and Co culture of cardiac myocytes and sympathetic neurons. In the process, NRG-1 beta incubation can enhance the efficacy of sympathetic nerve signal to cardiac myocytes by increasing the number of sympathetic neurites. The PI3K inhibitor LY294002 or ERK1/2 inhibitor PD98059 inhibits the effect of NRG-1 beta induced up-regulated expression of beta 1-AR and beta 2-AR and promoting the growth of neuronal protrusion. The results suggest that NRG-1 beta has the effect of further enhancement of sympathetic innervation signal to the fate of noradrenaline, which is mediated by the PI3K/Akt and ERK1/2 cell signal transduction pathways. The results of this study are targeted at the targeted treatment strategy based on the NRG-1 beta and its receptor signaling system. The formulation provides a theoretical basis and a theoretical basis for reference.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R54
本文编号：2155390
[Abstract]:The protective effect of new protective factors or new therapeutic strategies on cardiac muscle cell (CM) and its mechanism are of great significance for the treatment of heart disease and the improvement of cardiac function. Although many major breakthroughs have been made in the study of cardiac myocyte hypertrophy and ventricular remodeling, many research achievements have been made. Many of them are based on cardiac myocytes or ventricular structure itself, and the effect of the cardiac nerve regulation mechanism on the structure and function of cardiac myocytes remains to be studied from a broader and deeper level. The neuroregulatory protein -1 beta (neuregulin-1 beta, NRG-1 beta) can play a role in neurons by activating its tyrosine kinase receptor ErbB2 and ErbB4. A variety of regulatory functions, NRG-1 beta is likely to have the potential to play a unique regulatory role in the heart nerve. Up to now, there has been no discovery of the regulation of the NRG-1 beta by regulating the heart nerve. It is interesting that NRG-1 beta can also play an important regulatory function on cardiac myocytes. All the cells are the target tissues directly regulated by NRG-1 beta, which will make the regulatory mechanism of NRG-1 beta more complex. This topic will be based on a series of experimental studies based on the above research background. First, the ErbB2 and ErbB4 receptors of NRG-1 beta cultured neonatal rat cardiomyocytes and their downstream inositol -3- kinase (phosphoi) are studied. Nositide-3 kinase, PI3K) / protein kinase B (protein kinase B, PKB, Akt) and the expression of extracellular signal regulated kinase 1/2 (extracellular signal-regulated) and its effect on activation; secondly, the effect of beta and its related signal pathways on the important morphological and functional indexes of cardiac myocytes; Finally, using the cardiomyocytes with selective sympathetic innervation, the dual regulatory role of NRG-1 beta and its related signaling pathway on the nerve and myocardium is studied. Through the above series of studies, the role and mechanism of NRG-1 beta regulating cardiac myocytes directly or regulating the innervation of the cardiac myocytes by regulating their innervation are further elucidated. A new therapeutic strategy is proposed to enhance the ability or function of cardiac myocyte regeneration not only through the activity of NRG-1 beta and its receptor signal, but also through the regulatory role of the cardiac nerve in the NRG-1 beta and its receptor signaling system. Experimental study of white -1 beta activation of its receptor and its downstream signaling pathway in cardiac myocytes: NRG-1 beta activation of ErbB2 and ErbB4 receptors and its downstream PI3K/Akt and ERK1/2 is an important pathway for its biological effects. In order to study the expression of NRG-1 beta on ErbB2 and ErbB4 receptors and the downstream signaling molecules Akt and ERK1/2 expression of NRG-1 beta The effect of NRG-1 beta incubation and continuous incubation on the expression and activation of these molecules was observed by the cultured neonatal rat cardiomyocytes. The results showed that the acute incubation of NRG-1 beta did not affect the surface area of cardiac myocytes, while NRG-1 beta incubation could increase the myocardial cells. The surface area is beneficial to the growth and development of cardiac myocytes; the acute incubation of NRG-1 beta can not promote the expression of its receptor ErbB2 and ErbB4 and their downstream signal molecules Akt and ERK1/2, but can significantly increase their phosphorylation level. It indicates that the acute incubation of NRG-1 beta can activate its receptor and its related downstream cell signal transduction pathway; NRG-1 beta incubates continuously. It can not only promote the expression of its receptor ErbB2 and ErbB4 and their downstream signal molecules Akt and ERK1/2, but also increase their phosphorylation level significantly, thus improving the growth state of cardiac myocytes; the growth effect of NRG-1 beta myocytes can be blocked by PI3K inhibitor LY294002 or ERK1/2 inhibitor PD98059, but can not block the induction of NRG-1 beta. The effects of receptor ErbB2 and ErbB4 expression and phosphorylation show that NRG-1 beta acute incubation and NRG-1 beta incubation have different biological effects on cardiac myocytes with different biological effects of.NRG-1 beta incubation and NRG-1 beta incubation on the different biological effects of ErbB2 and ErbB4 and its downstream signal molecules Akt and ERK1 /2 expression and activation. The different treatment strategies may be taken in the future using NRG-1 beta for the treatment of corresponding cardiac disorders. The role of the second part of the neuromodulation protein -1 beta to improve the structure and function of cardiac myocytes is involved in the myosin heavy chain (myosin heavy chain, MHC), which can stimulate the light chain (myosin regulatory lig) of the myosin (myosin regulatory lig). The myocardial specific myosin light chain kinase (cardiac-specific myosin light-chain kinase, cMLCK) of HT chain, rMLC is an important factor regulating the assembly of myosine, the main gated channel of cardiac myocytes is the L- type calcium channel (L-type calcium channel) is the main channel to enter the cardiac myocytes, and the calcium ion three phosphate gland of the sarcoplasmic reticulum Sarco (Endo) plasmic reticulum Ca2+ ATPases or sarco (Endo) plasmic reticulum-Ca2+ pump, which regulates the coordination of contractile and diastolic circulation by transferring the cytoplasm to the sarcoplasmic reticulum. The above index is the key to the structure and function of the cardiac myocytes. Key factors, in order to detect the effect of NRG-1 beta on these indexes and their related mechanisms, we used the cultured neonatal rat cardiomyocytes to study the effects of NRG-1 beta and related signal pathways on these important morphological and functional indexes of cardiac myocytes, and the improvement of NRG-1 beta to improve the internal group of cardiac myocytes. The results showed that NRG-1 beta could promote the representative structural index MHC of cultured cardiac myocytes, the key kinase cMLCK in the cardiac myocytes, the expression of L- type calcium channel and SERCA2a, the P13K inhibitor LY294002 or ERK1/2 inhibitor PD98059 could inhibit the MHC, cMLCK, and calcium channel induced by NRG-1 beta. These results suggest that NRG-1 beta can effectively promote the expression of the basic structural molecules and functional molecules of cardiac myocyte contraction, thus improving the intrinsic composition of cardiac myocytes and thereby enhancing the potential ability of cardiac myocyte function, which is an effective treatment for NRG-1 beta in the future to improve cardiac function. The third part of the neuromodulation protein -1 beta enhances the fate of noradrenalin in cardiac myocytes, the fate of noradrenalin in cardiac myocytes is the prerequisite to guarantee and maintain the function of cardiac myocytes. On this basis, the function regulation of cardiac myocytes depends on the control of normal sympathetic nerve. The expression of adrenergic receptor (beta -adrenergic receptor, beta -AR) is an important manifestation of the fate of noradrenalin in cardiac myocytes. The activation of beta -AR is a must by the transmission of sympathetic innervation signal. This subject will establish an organotypic neck based on the dual regulatory effect of NRG-1 beta and its related signal pathways on the nerve and myocardium. A joint culture system of the superior cervical ganglion (SCG) tissue and scattered myocardial cells to study the cultured cardiac myocytes with or without sympathetic innervation, and then add NRG-1 beta incubation to change the fate potential of norepinephrine in the cardiomyocytes. The results show that NRG-1 beta incubation can make myocardial cells beta 1-AR. And the expression level of beta 2-AR was up-regulated, and the effect of selective sympathetic innervation on the up regulation of beta 1-AR and beta 2-AR expression was more obvious. NRG-1 beta incubation could further enhance the promotion effect of sympathetic innervation signal on the up regulation of the expression level of beta and beta 2-AR in cardiac myocytes, and Co culture of cardiac myocytes and sympathetic neurons. In the process, NRG-1 beta incubation can enhance the efficacy of sympathetic nerve signal to cardiac myocytes by increasing the number of sympathetic neurites. The PI3K inhibitor LY294002 or ERK1/2 inhibitor PD98059 inhibits the effect of NRG-1 beta induced up-regulated expression of beta 1-AR and beta 2-AR and promoting the growth of neuronal protrusion. The results suggest that NRG-1 beta has the effect of further enhancement of sympathetic innervation signal to the fate of noradrenaline, which is mediated by the PI3K/Akt and ERK1/2 cell signal transduction pathways. The results of this study are targeted at the targeted treatment strategy based on the NRG-1 beta and its receptor signaling system. The formulation provides a theoretical basis and a theoretical basis for reference.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R54
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