心交感神经重塑及碳纳米管对钾通道的影响及其机制研究
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摘要
心脏交感神经重塑主要表现为区域性的交感神经密度增加或者缺失(去神经)，可见于多种疾病。研究发现心脏交感神经重塑可明显增加心律失常的易感性，然而其发生机制目前还了解很少。本论文的第一部分工作主要从两方面来探讨心脏交感神经重塑增加室颤易感性的钾通道机制。一方面旨在阐明我们提出的“去交感神经降低I_(to)电流、增加室颤易感性”的观点。研究内容包括①去交感神经后心肌细胞I_(to)电流及其通道表达的变化；②这些变化对于室颤易感性的影响；③导致I_(to)下调可能的信号转导通路。基于这些设想，我们建立了大鼠去交感神经模型，利用乙醛酸染色、高压液相、RT-PCR、Western blot、全细胞膜片钳、Langendorff离体心脏灌流、心电指标检测等方法进行验证。结果发现，去交感神经①降低心脏组织的交感神经密度及NE浓度；②降低Kv4．2，Kv1．4、KChIP2蛋白水平；③降低I_(to)电流并使其激活曲线右移；④减小ERK1／2及CREB的磷酸化水平；⑤增加室颤的发生率。去交感神经恢复组NE浓度、Kv4．2、KChIP2表达及I_(to)电流均有所恢复，室颤的发生率降低。以上结果表明，去交感神经通过下调心肌细胞I_(to)通道的表达及电流强度，从而增加室颤的易感性；ERK1／2和CREB是参与这一过程的重要信号蛋白。
另一方面，我们实验室前期的研究结果表明心脏交感神经再生后促离子型谷氨酸受体(NMDA受体)表达上调，但NMDA受体与心律失常的关系目前仍不清楚，我们推测NMDA受体激活后可能影响心肌细胞I_(to)电流及其通道的表达，继而影响心脏电生理活动，从而增加心律失常的易感性。我们应用不同浓度的NMDA作用于原代培养的心肌细胞，利用全细胞膜片钳、Western blot、分光光度法、Langendorff离体心脏灌等方法，结果发现，不同浓度的NMDA作用于心肌细胞后①I_(to)通道的电流密度剂量依赖性地降低，激活速度减慢；②Kv4．2、Kv1．4及KChIP2蛋白表达水平明显降低；③线粒体呼吸链复合物Ⅰ、Ⅱ、Ⅲ和Ⅳ的活性降低；④细胞ATP的生成减少；⑤室颤的易感性明显增加。以上结果表明，NMDA受体激动可以降低I_(to)通道的电流密度及其通道蛋白表达，抑制线粒体能量代谢，导致线粒体功能紊乱，细胞膜的流动性降低结构异常，从而增加室颤的易感性。
碳纳米管是目前纳米材料研究的热点之一，但碳纳米管对细胞电生理活动的影响目前资料极少。本论文的第二部分工作研究碳纳米管对PC12细胞瞬时外向钾电流(I_(to))，外向整流钾电流(I_K)，内向整流钾电流(I_(K1))的影响及其机制。我们利用膜片钳、流式细胞仪、激光共聚焦等方法，研究发现碳纳米管①降低PC12细胞I_(to)、I_K、I_(K1)的电流密度；②降低线粒体膜电位；③增加细胞内游离钙的含量。以上结果表明，碳纳米管降低PC12细胞I_(to)、I_K、I_(K1)的电流密度，这可能与碳纳米管造成细胞氧化应急损伤及线粒体功能降低有关。
Cardiac sympathetic nerve remodeling is frequently observed in many diseases. However the mechanisms underlying sympathetic nerve remodeling-associated cardiac electrophysiological instability and ventricular fibrillation are not well understood. One aim of our study was to investigate the linkage of sympathetic denervation, K+ channel remodeling and cardiac arrhythmia. We developed a rat model of chemical sympathectomy by subcutaneous injections of 6-hydroxydopamine (6-OHDA). Cardiac sympathetic innervation was visualized by a glyoxylic catecholaminergic histofluorescence method. Transient outward current (I_(to)) of ventricular myocytes was recorded with the whole-cell configuration of the patch clamp technique. We found that sympathectomy 1) decreased cardiac sympathetic nerve density and norepinephrine level; 2) reduced the protein expression of Kv4.2, Kv1.4 and Kv channel-interacting protein 2 (KChIP2); 3) decreased current densities and delayed activation of I_(to) channels; 4) reduced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB); and 5) increased the severity of ventricular fibrillation induced by rapid pacing. Three weeks after 6-OHDA injections to allow sympathetic regeneration, cardiac sympathetic nerve density and norepinephrine level, expression levels of Kv4.2, KChIP2 proteins and I_(to) current densities were partially normalized and ventricular fibrillation severity was decreased. We conclude that chemical sympathectomy downregulates the expression of selective Kv channel subunits and decreases myocardial I_(to) channel activities, contributing to the elevated susceptibility to ventricular fibrillation.
A second aim of this study was to investigate the effect of NMDA receptor activation on I_(to) Channel activity. We previously found that the expression of myocardial NMDA receptors were significantly upregulated in a rat model of cardiac nerve sprouting. Based on these findings, we investigated the relationship of NMDA recepor activation and I_(to) current. We incubated cardiomyoctes from 10-14-day rats with NMDA, and recorded the I_(to) current of these cells with whole-cell configuration of patch clamp technique. We further investigated the effects of NMDA on the activities of the four complexes of the respiratory chain in the mitochondria using fluorometer and estimated the production of ATP by bioluminescent methods. The results showed that acute treatment with NMDA suppressed the activities of the four complexes of the respiratory chain and reduced the production of ATP in the mitochondria of rat cardiomyoctes. These results suggest that NMDA receptor activation decreases myocardial I_(to) channel activities, suppresses the energy metabolism and induces mitochondrial dysfunction, contributing to the elevated susceptibility to ventricular fibrillation.
A third aim of this study was to observe the effect of carbons nanotubes on K+ channels on PC12 cells. Nowadays, carbon nanotube research is one of the hotspots in nano research and was considered a potential carrier of drugs and vaccines. However, the side effects of carbon nanotubes are less known. For example, the interaction between carbon nanotubes and cell ion channels is still not well established. In this study, we investigated the effect of multile-walled carbon nanotubes (MWNT) on three types of K+ currents (I_(to), I_K and I_(K1)) in PC12 cells. We incubated PC12 cells with MWNT and recorded the I_(to), I_K, I_(K1) currents of PC12 cells at different times with whole-cell configuration of the patch clamp technique. We also investigated the effects of MWNT on mitochondrial membrane potential (ΔΨm) and intracellular calcium ([Ca~(2+)]_i) level. We found thatMWNT 1) decreased the current densities of I_(to), I_K and I_(K1), 2) increased the [Ca~(2+)]_i and 3)reduced mitochondrial membrane potential (ΔΨm). These results suggest that MWNT in aqueous suspension could suppress potassium channel activities in undifferentiated PC12 cells, and these effects may be associated with mitochondrial dysfunction and oxidativestress.
另一方面，我们实验室前期的研究结果表明心脏交感神经再生后促离子型谷氨酸受体(NMDA受体)表达上调，但NMDA受体与心律失常的关系目前仍不清楚，我们推测NMDA受体激活后可能影响心肌细胞I_(to)电流及其通道的表达，继而影响心脏电生理活动，从而增加心律失常的易感性。我们应用不同浓度的NMDA作用于原代培养的心肌细胞，利用全细胞膜片钳、Western blot、分光光度法、Langendorff离体心脏灌等方法，结果发现，不同浓度的NMDA作用于心肌细胞后①I_(to)通道的电流密度剂量依赖性地降低，激活速度减慢；②Kv4．2、Kv1．4及KChIP2蛋白表达水平明显降低；③线粒体呼吸链复合物Ⅰ、Ⅱ、Ⅲ和Ⅳ的活性降低；④细胞ATP的生成减少；⑤室颤的易感性明显增加。以上结果表明，NMDA受体激动可以降低I_(to)通道的电流密度及其通道蛋白表达，抑制线粒体能量代谢，导致线粒体功能紊乱，细胞膜的流动性降低结构异常，从而增加室颤的易感性。
碳纳米管是目前纳米材料研究的热点之一，但碳纳米管对细胞电生理活动的影响目前资料极少。本论文的第二部分工作研究碳纳米管对PC12细胞瞬时外向钾电流(I_(to))，外向整流钾电流(I_K)，内向整流钾电流(I_(K1))的影响及其机制。我们利用膜片钳、流式细胞仪、激光共聚焦等方法，研究发现碳纳米管①降低PC12细胞I_(to)、I_K、I_(K1)的电流密度；②降低线粒体膜电位；③增加细胞内游离钙的含量。以上结果表明，碳纳米管降低PC12细胞I_(to)、I_K、I_(K1)的电流密度，这可能与碳纳米管造成细胞氧化应急损伤及线粒体功能降低有关。
Cardiac sympathetic nerve remodeling is frequently observed in many diseases. However the mechanisms underlying sympathetic nerve remodeling-associated cardiac electrophysiological instability and ventricular fibrillation are not well understood. One aim of our study was to investigate the linkage of sympathetic denervation, K+ channel remodeling and cardiac arrhythmia. We developed a rat model of chemical sympathectomy by subcutaneous injections of 6-hydroxydopamine (6-OHDA). Cardiac sympathetic innervation was visualized by a glyoxylic catecholaminergic histofluorescence method. Transient outward current (I_(to)) of ventricular myocytes was recorded with the whole-cell configuration of the patch clamp technique. We found that sympathectomy 1) decreased cardiac sympathetic nerve density and norepinephrine level; 2) reduced the protein expression of Kv4.2, Kv1.4 and Kv channel-interacting protein 2 (KChIP2); 3) decreased current densities and delayed activation of I_(to) channels; 4) reduced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB); and 5) increased the severity of ventricular fibrillation induced by rapid pacing. Three weeks after 6-OHDA injections to allow sympathetic regeneration, cardiac sympathetic nerve density and norepinephrine level, expression levels of Kv4.2, KChIP2 proteins and I_(to) current densities were partially normalized and ventricular fibrillation severity was decreased. We conclude that chemical sympathectomy downregulates the expression of selective Kv channel subunits and decreases myocardial I_(to) channel activities, contributing to the elevated susceptibility to ventricular fibrillation.
A second aim of this study was to investigate the effect of NMDA receptor activation on I_(to) Channel activity. We previously found that the expression of myocardial NMDA receptors were significantly upregulated in a rat model of cardiac nerve sprouting. Based on these findings, we investigated the relationship of NMDA recepor activation and I_(to) current. We incubated cardiomyoctes from 10-14-day rats with NMDA, and recorded the I_(to) current of these cells with whole-cell configuration of patch clamp technique. We further investigated the effects of NMDA on the activities of the four complexes of the respiratory chain in the mitochondria using fluorometer and estimated the production of ATP by bioluminescent methods. The results showed that acute treatment with NMDA suppressed the activities of the four complexes of the respiratory chain and reduced the production of ATP in the mitochondria of rat cardiomyoctes. These results suggest that NMDA receptor activation decreases myocardial I_(to) channel activities, suppresses the energy metabolism and induces mitochondrial dysfunction, contributing to the elevated susceptibility to ventricular fibrillation.
A third aim of this study was to observe the effect of carbons nanotubes on K+ channels on PC12 cells. Nowadays, carbon nanotube research is one of the hotspots in nano research and was considered a potential carrier of drugs and vaccines. However, the side effects of carbon nanotubes are less known. For example, the interaction between carbon nanotubes and cell ion channels is still not well established. In this study, we investigated the effect of multile-walled carbon nanotubes (MWNT) on three types of K+ currents (I_(to), I_K and I_(K1)) in PC12 cells. We incubated PC12 cells with MWNT and recorded the I_(to), I_K, I_(K1) currents of PC12 cells at different times with whole-cell configuration of the patch clamp technique. We also investigated the effects of MWNT on mitochondrial membrane potential (ΔΨm) and intracellular calcium ([Ca~(2+)]_i) level. We found thatMWNT 1) decreased the current densities of I_(to), I_K and I_(K1), 2) increased the [Ca~(2+)]_i and 3)reduced mitochondrial membrane potential (ΔΨm). These results suggest that MWNT in aqueous suspension could suppress potassium channel activities in undifferentiated PC12 cells, and these effects may be associated with mitochondrial dysfunction and oxidativestress.
引文
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