缝隙连接与心脏的传导

细胞之间动作电位或兴奋的传导称为胞间传导 ,可兴奋细胞间的电耦联是通过一种特殊的胞间结构而实现 ,这种结构即是缝隙连接 (gapjunction ,GJ)。现已证实 ,心脏的正常传导和引起心律失常的异常传导都与缝隙连接直接相关。目前 ,缝隙连接是心电学基础与临床研究的共同热点。一、缝隙连接的基本概念心肌细胞间的连接主要由闰盘 (intercalateddisk)构成。闰盘由桥粒 (desmosome)、粘附膜 (fasciaadherents)和缝隙连接三部分组成。桥粒是紧密贴附在一起的细胞膜 ,能将各个心肌细胞紧密连接在一起 ,其功能目前尚不明了 ,但其电阻很高 ,离子很难…     

心脏细胞的缝隙连接与心律失常

缝隙连接（Ｇａｐｊｕｎｃｔｉｏｎ，ＧＪ）是普遍存在于心肌细胞、肝细胞、肠平滑肌细胞、晶状体细胞和一些神经元细胞间的一种细胞间通道。近年来随着对其研究的深入，ＧＪ与心血管疾病的关系，尤其是ＧＪ在心律失常发生中的作用正备受关注，本文就此作一综述。１ＧＪ的...     

缝隙连接与传导异常型心律失常

缝隙连接 (ｇａｐｊｕｎｃｔｉｏｎ)是一个古老的结构 ,广泛存在于各种生物体的多个组织器官中。在心肌细胞中主要存在于闰盘 (ｉｎｔｅｒｃａｌａｔｅｄｄｉｓｃ) ,闰盘处有 3种结构连接相邻细胞[1] 。(1)桥粒 (ｄｅｓｍｏｓｏｍｅ) :由相邻两个细胞膜上各自延伸的糖蛋白 (ｇｌｙｃｏｐｒｏｔｅｉｎｓⅠⅡⅢ )相互连接 ,在每个细胞膜上发出这些糖蛋白处其根部密集排列形成的致密斑连同糖蛋白一起被称作桥粒 ;(2 )粘连膜 (ｆａｓｃｉａａｄｈｅｓｉｏｎ) :仍由相邻两个细胞膜上各自延伸的糖蛋白相互连接构成 ,其中探明的一种为钙粘附因子 (…     

心脏缝隙连接和心律失常

心脏缝隙连接是心肌细胞间直接联系并交换信息的重要途径 ,它的分布及功能对于心肌的电传播起着重要作用。在许多心脏疾病中 ,心肌组织都有缝隙连接的改变 ,这种改变似与心律失常的易发性有关。缝隙连接与心律失常之间是相互作用 ,相互影响的。人们正将缝隙连接作为新的药物作用靶点进行研究 ,以期找到对抗心律失常的新方法。     

心肌细胞缝隙连接及其与心血管疾病和心律失常的关系

心肌细胞缝隙连接 (GJ)提供细胞间的电流通路 ,使动作单位协同扩布。心肌细胞的缝隙连接蛋白 (Cx)主要有Cx4 0、Cx4 3和Cx4 5 ,其在心脏中的分布和功能不同。在有疾病的心肌中 ,Cx含量和GJ分布发生改变 ,主要受酶、机械力等因素的调控 ,最终导致功能上的改变。Cx含量的减少、GJ密度减低及GJ的侧边化导致区域内各向异传导性变化 ,与心律失常的产生有关     

心肌细胞缝隙连接与心律失常的关系

有疾病的心肌中缝隙连接(GJ)发生重塑,连接蛋白(Cxs)含量的改变和ID内GJ斑的分布发生变化,从而使心肌细胞间电耦联传导速度减慢,各向异比率减小增加折返性心律失常,有助于阐明一些心律失常机制.     

缝隙连接蛋白与心律失常的相关性研究进展

以往认为心律失常的发生主要与心肌细胞兴奋性异常有关但近年来的研究表明细胞间电耦联障碍是心律失常的另一个重要原因之一,其所起的致心律失常作用甚至大于兴奋性异常。由心肌缝隙连接蛋白(connexin,Cx)构成的缝隙连接(gapjunction,GJ)通道是心肌细胞之间的一种特殊连接通道,     

缝隙连接、连接蛋白43及其与心律失常的关系

缝隙连接(GJ)通道是介导心肌细胞间电化学信息交流,保证心脏整体活动的协调性和同步性的特殊通道。在致心律失常发生上,GJ通道介导的细胞间电耦联障碍甚至比膜离子通道功能紊乱起了更重要的作用。连接蛋白43(Cx43)是心室GJ通道的主要构成成份,其表达和分布的异常将导致心室肌细胞的整体性异常,从而传导速度和传导各向异性发生改变,产生折返和传导阻滞。以GJ通道为作用靶点的新一代抗心律失常药的出现将为心律失常的治疗带来新的希望。     

异型缝隙连接通道和磷酸化对心脏缝隙连接的调变

目的 检测由缝隙连接蛋白(connexin，Cx)43和Cx45组成的多种异型缝隙连接通道(her—eromultimeric gap junction channels，HGJC)和磷酸化对缝隙连接(gap junction，GJ)的调变作用。方法 将转染了编码为Cx43或Cx45的DNA后的Hela细胞放置在一起共同培养组成双侧和单侧异型GJ通道。显微注射若丹明123(rhodamine123，Rh)检测经200nmol／L十四(烷)酰佛波醇乙酸酯(12-0-tetrade—canoylphorbol-13-acetae，TPA)处理前后，在紫外光显示下由Cx43和Cx45所组成的不同GJ通道对荧光染料的偶联率(coupling ratio)。结果 在不同的GJ中，同型GJ通道Cx43(homotypie Cx43，HoCx43)偶联率最高。从Cx45侧注入荧光染料的单侧异型GJ通道45(mono-heteromeric Cx45-Cx43／45，MH45)偶联率较之从Cx43／45侧注入荧光染料的MH45、双侧异型GJ通道Cx43／45(bi-heteromeric Cx43／45，BH43／45)及同型GJ通道Cx45(homotypic Cx45，HoCx45)等的偶联率是最低的。根据HoCx43或HoCx45通道的偶联率对各型通道偶联率进行标准化处理。BH43／45和MH43通道的偶联率均较HoCx43降低。对MH45通道来说，从Cx43／45侧注射的通道偶联率大于从Cx45侧注射的偶联率。TPA处理后HoCx43的偶联率降低，而当Cx43和Cx45组合成BH43／45和MH43通道后其偶联率下降更显著。结论 Cx43和Cx45共同表达可构成BH43／45、MH43和MH45等异型通道，而这些通道可降低细胞间的通讯并对磷酸化的作用不敏感。单侧异型GJ通道的偶联率取决于染料注射的方向。     

膜离子通道及缝隙连接在心律失常中的作用

心肌细胞膜离子通道是其电活动的基础,各种原因所致的Na+、K+、Ca2+通道异常改变可产生多种心律失常。近年研究发现,心肌细胞间缝隙连接功能障碍同样是引起心律失常的一个重要因素。对缝隙连接进行恰当的药物干预,也能取得明显的抗心律失常作用。     

缝隙连接重构和室性心律失常

缝隙连接是心肌细胞间直接联系并交换信息的重要途径,在许多心脏疾病中,心肌组织都有缝隙连接的改变,即缝隙连接的重构。缝隙连接的含量、分布及自身磷酸化状态的改变与室性心律失常的发生密切相关。缝隙连接重构与电重构和自主神经之间可能有密切关系。仅仅应用以缝隙连接为靶点的抗心律失常的药物可能是不够的。     

Physiological Modulation of Cardiac Gap Junction Channels

Cardiac Gap Junction Channel Regulation. Synchronization of pacemaker activity and cardiac action potential propagation is dependent upon the maintenance of electrical communication via gap junctions. Gap junction channels in mammalian heart are formed by a 43-kilodalton (kD) protein, connexin43, and have a unitary conductance of 50 picosiemens (pS). In embryonic chick heart, three gap junction proteins of 42, 43, and 45 kD have been cloned, the functional properties of which have not been individually identified. Unitary channel conductances ranging from 40-240 pS have been reported, but conductances of 40-80 and 160 pS are most frequently observed in embryonic chick heart. Developmental changes in transjunctional voltage dependence are known to occur and may be correlated with differential expression of the three chick connexins during development. Gap junction conductance (g_j) is highly regulated, being maintained or increased by ATP and cAMP-dependent pathways. Conversely, g_j is reduced by treatment with various lipophilic agents (e.g., n-alkanols, arachidonic acid, halothane), large transjunctional potentials, increasing intracellular cation (e.g., H⁺, Ca²⁺) concentrations, and tyrosine phophorylation of rat connexin43. It is unclear at this time if any of the regulatory mechanisms can mediate beat-to-beat fluctuations in g_j of normal myocardium. Most available evidence indicates that this modulation occurs by the open-closed gating of individual channels rather than effects on the unitary channel conductance. The precise molecular mechanisms are not yet known, but the functional expression of gap junction proteins should allow for determination of the functional domains responsible for direct and indirect modulation of the cardiac gap junction proteins.     

兰尼碱受体2调节及其与心律失常的关系

兰尼碱受体2是广泛存在于肌浆网上的Ca2+释放通道,受到多种因子的调节,兰尼碱受体2参与心肌细胞的兴奋-收缩耦联,兰尼碱受体2的结构或调节异常与心力衰竭及致死性心律失常的发生关系密切。现对兰尼碱受体2的结构、调节及其在心律失常中的作用机制作一阐述。     

心肌肥大时间隙连接分布的改变及其对传导特性的影响

目的 探讨压力超负荷所致左室心肌肥大时间隙连接(GJ)分布的改变及其对兴奋冲动传导特性的影响。方法 12只犬随机分为正常对照组(n=4)和主动脉缩窄组(n=8);主动脉缩窄组通过缩窄腹主动脉4周而形成左室心肌肥大,对照组则仅行假手术;应用心外膜标测法测定左室心肌传导速度;应用激光共聚焦显微镜技术和荧光免疫组织化学方法对肥大心肌间隙连接的主要成分连接蛋白43(connexin43,Cx43)进行定量研究。结果(1)主动脉缩窄组和对照组左室心肌细胞总的Cx43表达量无明显差异;(2)对照组心肌细胞端对端连接处Cx43的表达量与侧对侧连接处的Cx43表达量的比值为(1.43±0.18),主动脉缩窄组的比值为(0.72±0.08),两组之间存在显著性差异(P<0.01);(3)对照组左室心肌纵向传导速度与横向传导速度比为(3.20±0.28),主动脉缩窄组的比为(2.48±0.25),两组之间存在显著性差异(P<0.01)。结论 压力超负荷所致的左室心肌肥大可出现间隙连接分布模式的改变和兴奋冲动在心室肌传导的各向异性增大,这种改变可能是心肌肥大时常伴发心律失常的重要原因之一。     

Junctional Communication Between Isolated Pairs of Canine Atrial Cells is Mediated by Homogeneous and Heterogeneous Gap Junction Channels

Heterogeneous Cardiac Gap Junction Channels. Introduction: The expression of multiple connexins (Cxs) in the canine right atria raises the possibility that heterogeneous gap junction channels might he formed.
Methods and Results: We compared the unitary conductance (γ_j) of gap junction channels between isolated canine atrial cell pairs with those of homogeneous cardiac gap junction channels expressed in other systems. After partial uncoupling with halothane (2 mmol/L), the γ_j calculations for atrial isolated cardiocytes ranged from 30 to 220 pS and their distribution in event histograms was spread over the entire range, with a small peak at ∼100 pS. This distribution deviates from the discrete peaks calculated from γ_j of homogeneous channels. All–points histograms of junctional current traces revealed distinct open–state levels. Some of these are related to the main open state of connexin43 (Cx43) (∼100 pS), observed between canine ventricular cells, or connexin40 (Cx40) (∼215 pS) observed between transfected N2A cells under similar recording conditions. Intermediate values for γ_j were not observed in recordings from ventricular cells, which express mostly Cx43, nor in those from N2A cells expressing Cx40, but were observed consistently between atrial cells. Because they were measured as first openings from the nonconductance state, these intermediate values most likely represent main conductance states of heterogeneous channels rather than subconductance states of homogeneous channels.
Conclusion: This suggests that regulation of cell–to–cell coupling in the heart depends not only on posttranslational modulation of preexisting Cxs, but also on the intracellular assembly mechanisms, and the way individual Cxs interact with others within a connexon and/or with other connexons from adjacent cells.     

血管肌内皮缝隙连接的功能

血管内皮细胞和平滑肌细胞间存在着肌内皮缝隙连接,内皮细胞除通过释放血管活性物质影响下方平滑肌细胞的活动外,也可通过肌内皮缝隙连接调节平滑肌的功能,因此,肌内皮缝隙连接在血管功能调节中具有重要作用,并与病理状态下的血管功能异常有密切关系。     

心肌缝隙连接在缺血预适应中的作用

目的探讨心肌缝隙连接（GJ）在缺血预适应（IPC）心肌保护中的地位和作用。方法将72只大鼠分为缺血再灌注组（对照组）、IPC组、IPC＋5-羟基奎酸（5-HD）组、二氮嗪（Dia）组、Dia＋5-HD组、甘草次酸（GA）组、GA＋5-HD组、GA＋IPC组,测量各组的血流动力学指标、心肌梗死面积和心律失常发生情况。结果与对照组相比,IPC组、Dia组、GA组能降低心肌梗死面积,减少心律失常,5-HD能阻断IPC和Dia的心肌保护作用,对GA无影响。IPC加用GA不能抑制IPC的保护作用。结论在IPC信号传导通路中,GJ位于线粒体ATP敏感性钾通道的下游,可能是IPC的终末效应器,但在IPC触发阶段不起作用。     

The Role of Myocardial Anisotropy in Arrhythmogenesis Associated with Myocardial Ischemia and Infarction

Myocardial Anisotropy in Ischemia and Infarction . Anisotropy is defined as any property of a system that differs depending on the direction in which it is measured. In the heart, the structure of the cardiac myocytes and their electrical coupling via gap junctions confer an anisotropy in the intracellular resistance to current flow in myocardial tissue. This in turn is responsible for anisotropy in conduction in which the velocity and uniformity of impulse conduction is dependent on its direction relative to the normal myocardial fiber orientation and any underlying pathological nonuniformities in cell orientation and coupling. How cells are coupled also influences refractoriness and excitability. Recent experimental evidence has implicated uniform and nonuniform myocardial anisotropy as important substrates that play a role in the initiation and maintenance of arrhythmias in the setting of ischemia and infarction. These studies may provide a focus for the development of new antiarrhythmic modalities that depend on the modulation of cell electrical coupling.     

缝隙连接阻滞剂预防缺血性室性心律失常及其机制的研究

目的观察缝隙连接阻滞剂类Heptanol对局部心肌缺血性室性心律失常发生率的影响,并探索可能的作用机制。方法①结扎离体SD大鼠冠状动脉前降支,造成左心室前壁局部缺血,观察不同浓度Heptanol对缺血所致室性心律失常发生率的影响。②取缺血部分心肌进行免疫荧光染色及RT PCR检测,应用图像分析系统半定量分析CX43蛋白及mRNA的水平。③实验动物随机分为5组,每组12只,分别为对照组、缺血组、0.1mMHeptanol组、0.3mMHeptanol组、0.5mMHeptanol组。结果①Heptanol可明显降低由于缺血引起的室性心动过速(室速)和心室颤动(室颤,缺血组45%;0.1mMHepta nol组10%;0.3mMHeptanol组0;0.5mMHeptanol组10;P<0.05)。②缺血心肌CX43蛋白表达面积比正常心肌明显减少,Heptanol可使缺血所致的CX43蛋白的减少发生部分逆转(对照组1706±397;缺血组561±147;0.1mMHeptanol组1027±215;0.3mMHeptanol组1112±301;0.5mMHeptanol组1179±425,P<0.05)。mRNA表达与蛋白水平的变化相一致。结论①Heptanol可以减少由于局部缺血引起的室速和室颤发生率。②Heptanol可以部分逆转缺血引起的CX43mRNA和蛋白表达下调。     

Gap Junction Protein Phenotypes of the Human Heart and Conduction System

Connexin Phenotypes in the Human Heart. Introduction: Gap junction channels are major determinants of intercellular resistance to current flow between cardiac myocytes. Alterations in gap junctions may contribute to development of arrhythmia substrates in patients. However, there is significant interspecies variation in the types and amounts of gap junction subunit proteins (connexins) expressed in disparate regions of mammalian hearts. To elucidate determinants of conduction properties in the human heart, we characterized connexin phenotypes of specific human cardiac tissues with different conduction properties. Methods and Results: The distribution and relative abundance of Cx37, Cx40, Cx43, Cx45, and Cx46 were studied immunohistochemically using monospecific antibodies and frozen sections of the sinoatrial node and adjacent atria, the AV node and His bundle, the bundle branches, and the left and right ventricular walls. Patterns of expression of these connexins in the human heart differed from those in previous animal studies. Sinus node gap junctions were small and sparse and contained Cx45 and apparently smaller amounts of Cx40 but no Cx43. AV node gap junctions were also small and contained mainly Cx45 and Cx40 hut, unlike the sinus node, also expressed Cx43. Atrial gap junctions were larger than nodal junctions and contained moderate amounts of Cx40, Cx43, and Cx45. Junctions in the bundle branches were the largest in size and contained abundant amounts of Cx40, Cx43, and Cx45. Gap junctions in ventricular myocardium contained mainly Cx43 and Cx45; only a very small amount of ventricular Cx40 was detected in subendocardial myocyte junctions and endothelial cells of small to medium sized intramural coronary arteries. Minimal Cx37 and Cx46 immunoreactivity was detected between occasional atrial or ventricular myocytes. Conclusions: The relative amounts of individual connexins and the number and size of gap junctions vary greatly in specific regions of the human heart with different conduction properties. These differences likely play a role in regulating cardiac conduction velocity. Differences in the connexin phenotypes of specific regions of the human heart and experimental animal hearts must he considered in future experimental or modeling studies of cardiac conduction.