Myofibroblasts induce ectopic activity in cardiac tissue
Myofibroblasts induce ectopic activity in cardiac tissue
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DOI：
10.1161/circresaha.107.160549
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发表时间：
2007-10-12
影响因子：
20.1
通讯作者：
Rohr, Stephan
中科院分区：
文献类型：
--
作者：
Miragoli, Michele;Salvarani, Nicolo;Rohr, Stephan
心肌组织中的局灶性异位活动是快速性心律失常发生和持续的关键因素。由于肌成纤维细胞存在于纤维化重塑的心肌和梗死瘢痕中，在体外通过缝隙连接通过异细胞电紧张性相互作用使心肌细胞去极化，我们使用包被肌成纤维细胞的培养的心室肌细胞链来研究这种相互作用是否会导致去极化诱导的异常自律性。虽然未包被的心肌细胞链总是静止的，但肌成纤维细胞以一种密度依赖的方式诱导同步自发活动。在空间肌成纤维细胞密度为15.7%时出现激活，在肌成纤维细胞密度为50%时涉及超过80%的制剂。自发活动建立在去极化诱导的自律性的基础上，表现为：(1)肌膜K-ATP通道开放剂P-1075抑制活动；(2)在去极化过程中，电流钳制的单个心肌细胞的活动被诱导到与心肌成纤维细胞在心肌细胞链上的诱发电位相似的电位；以及(3)被连接蛋白43基因修饰的Hela细胞而不是通讯缺陷的HeLa野生型细胞所包裹的心肌细胞链上的自发活动被诱导。除了揭示心肌细胞单层培养的标志，即自发电机械活动的潜在机制外，这些发现还开启了这样一个观点，即在压力超负荷和梗塞后，结构重塑的心肌中存在的肌成纤维细胞可能通过诱导异位活动而导致心律失常的发生。
Focal ectopic activity in cardiac tissue is a key factor in the initiation and perpetuation of tachyarrhythmias. Because myofibroblasts as present in fibrotic remodeled myocardia and infarct scars depolarize cardiomyocytes by heterocellular electrotonic interactions via gap junctions in vitro, we investigated using strands of cultured ventricular cardiomyocytes coated with myofibroblasts, whether this interaction might give rise to depolarization-induced abnormal automaticity. Whereas uncoated cardiomyocyte strands were invariably quiescent, myofibroblasts induced synchronized spontaneous activity in a density dependent manner. Activations appeared at spatial myofibroblast densities >15.7% and involved more than 80% of the preparations at myofibroblast densities of 50%. Spontaneous activity was based on depolarization-induced automaticity as evidenced by: (1) suppression of activity by the sarcolemmal K-ATP channel opener P-1075; (2) induction of activity in current-clamped single cardiomyocytes undergoing depolarization to potentials similar to those induced by myofibroblasts in cardiomyocyte strands; and (3) induction of spontaneous activity in cardiomyocyte strands coated with connexin 43 transfected Hela cells but not with communication deficient HeLa wild-type cells. Apart from unveiling the mechanism underlying the hallmark of monolayer cultures of cardiomyocytes, ie, spontaneous electromechanical activity, these findings open the perspective that myofibroblasts present in structurally remodeled myocardia following pressure overload and infarction might contribute to arrhythmogenesis by induction of ectopic activity.