Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing model using human induced pluripotent stem cell-derived ventricular cardiomyocytes.
Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing model using human induced pluripotent stem cell-derived ventricular cardiomyocytes.
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使用人诱导多能干细胞来源的心室心肌细胞的长期起搏模型中内质网应激增加导致的结构和电生理功能障碍
DOI：
10.1186/s13287-017-0566-6
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发表时间：
2017-05-11
影响因子：
7.5
通讯作者：
Chen M
中科院分区：
文献类型：
--
作者：
Cui C;Geng L;Shi J;Zhu Y;Yang G;Wang Z;Wang J;Chen M
长期心室起搏具有有害影响，并且当累积心室起搏百分比（Cum%VP）超过40%的时间时变得更加显著。然而，细胞紊乱和起搏导致心肌疾病的途径还不清楚。解决这些问题的尝试受到了难以获得人体心脏组织和无法在体外建立更持久（持续时间超过数周）的起搏模型的阻碍。将人诱导多能干细胞衍生的心室心肌细胞（VCM）在电刺激存在下培养2周。定量结构和电生理分析用于确定起搏的功能障碍。与对照组相比，起搏的VCM表现出收缩蛋白表达的显着减少，细胞凋亡率增加和电生理重构的Cum%VP依赖性的方式。蛋白质表达水平的调查显示，长期起搏普遍激活ER应激和下游钙蛋白酶。抑制钙蛋白酶可减轻对心室肌结构重构的不利影响，并增加心室肌起搏后的伊卡，L。结果表明，体外起搏心室肌2周可导致一系列结构和电生理功能障碍。ER应激和下游钙蛋白酶的增加可能是疾病发病机制的核心机制。这一发现可能代表了长期起搏患者管理的新治疗目标。本文的在线版本（doi：10.1186/s13287-017-0566-6）包含补充材料，可供授权用户使用。
Long-term ventricular pacing has deleterious effects and becomes more significant when cumulative percent ventricular pacing (Cum%VP) exceeds 40% of time. However, cellular disturbances and pathways by which pacing leads to myocardial disorders are not well understood. Attempts to resolve these questions have been hampered by difficulties in obtaining human cardiac tissue and the inability to build a longer-lasting (lasting longer than weeks) pacing model in vitro. Human induced pluripotent stem cell-derived ventricular cardiomyocytes (VCMs) were cultured in the presence of electrical stimulation for 2 weeks. Quantitative structural and electrophysiological analyses were used to define the functional disturbances of pacing. Compared to controls, paced VCMs exhibited a remarkable reduction in the contractile protein expression, an increased apoptosis ratio and electrophysiological remodelling in a Cum%VP-dependent manner. Investigation of the protein expression levels revealed that long-term pacing universally activated both ER stress and downstream calpain. Moreover, the inhibition of calpain attenuated the adverse effects on the structural remodelling and increased the ICa, L in paced VCMs. The results demonstrated that pacing VCMs for 2 weeks in vitro led to a series of structural and electrophysiological dysfunctions. The increased ER stress and downstream calpain could be a central mechanism underlying the disease pathogenesis. This finding could represent a new therapeutic target in the management of long-term pacing patients. The online version of this article (doi:10.1186/s13287-017-0566-6) contains supplementary material, which is available to authorized users.