Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin
Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin
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DOI：
10.1161/01.res.0000089258.40661.0c
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发表时间：
2003-09-05
影响因子：
20.1
通讯作者：
Rohr, S
中科院分区：
文献类型：
--
作者：
Gaudesius, G;Miragoli, M;Rohr, S
大约一半的心脏细胞由非心肌细胞组成，其中成纤维细胞代表主要细胞类型。众所周知，培养中的单个心肌细胞和成纤维细胞在单细胞水平上建立间隙连接通讯（短程相互作用）。然而，尚不清楚这种耦合是否允许长距离激活心脏组织（长程相互作用）。长程相互作用可能负责心脏移植后供体和受体组织的电同步，并可能在心律失常发生中发挥作用。使用一种新型异细胞培养模型研究了这个问题，该模型中心肌细胞链被心脏成纤维细胞在规定的距离内打断。通过使用光学记录技术，可以证明脉冲沿成纤维细胞插入物的传播在长达 300 μm 的距离内是成功的，并且其特征在于长度相关的局部传播延迟范围为 11 至 68 ms（表观局部“传导速度”4.6 +/- 1.8 mm/s，n = 23）。通过显示由通讯缺陷的 HeLa 细胞组成的插入物无法支持增殖，排除了机械拉伸参与这种现象的可能性。相比之下，表达 connexin43 的 HeLa 细胞允许脉冲传导距离长达 600 微米。免疫细胞化学显示成纤维细胞和心肌细胞表达connexin43和connexin45，而connexin40不表达。这些结果表明，心脏来源的成纤维细胞能够通过电紧张相互作用在长距离上同步多细胞心脏组织的电活动。这种同步伴随着极大的局部传导延迟，这可能导致纤维化心脏中心律失常的产生。
Roughly half of the cells of the heart consist of nonmyocardial cells, with fibroblasts representing the predominant cell type. It is well established that individual cardiomyocytes and fibroblasts in culture establish gap junctional communication at the single cell level (short-range interaction). However, it is not known whether such coupling permits activation of cardiac tissue over extended distances (long-range interaction). Long-range interactions may be responsible for electrical synchronization of donor and recipient tissue after heart transplantation and may play a role in arrhythmogenesis. This question was investigated using a novel heterocellular culture model with strands of cardiomyocytes interrupted by cardiac fibroblasts over defined distances. With use of optical recording techniques, it could be shown that impulse propagation along fibroblast inserts was successful over distances up to 300 mum and was characterized by length-dependent local propagation delays ranging from 11 to 68 ms (apparent local "conduction velocities" 4.6 +/- 1.8 mm/s, n = 23). Involvement of mechanical stretch in this phenomenon was excluded by showing that inserts consisting of communication-deficient HeLa cells were incapable of supporting propagation. In contrast, HeLa cells expressing connexin43 permitted impulse conduction over distances as long as 600 mum. Immunocytochemistry showed that fibroblasts and cardiomyocytes expressed connexin43 and connexin45, whereas connexin40 was absent. These results illustrate that fibroblasts of cardiac origin are capable of synchronizing electrical activity of multicellular cardiac tissue over extended distances through electrotonic interactions. This synchronization is accompanied by extremely large local conduction delays, which might contribute to the generation of arrhythmias in fibrotic hearts.