基质刚度通过通道动力学调制减轻心肌细胞脱极化斜率
Yuan Zhu1, Sheng-An Su1, Jixie Le1
1Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, 310009, China; Transvascular Implantation Devices Research Institute, Hangzhou, 310053, China.
Archives of biochemistry and biophysics
|November 2, 2025
概括
由于细胞外基质 (ECM) 沉积导致心脏组织硬化,会损害心肌细胞脱极化,并通过改变通道 (Nav1.5) 功能来促进心律失常. 这项研究揭示了心肌纤维化中心律失常的关键机电机理.
科学领域:
- 心血管研究研究心血管研究
- 生物医学工程 生物医学工程
- 心脏电生理学 心脏电生理学
背景情况:
- 在心脏组织中过度的细胞外基质 (ECM) 沉积会增加心肌硬度.
- 心肌硬度增加与腹功能障碍和心律失常风险有关.
- 连接ECM沉积与心律失常的精确电机械机制尚未完全理解.
研究的目的:
- 调查ECM介导的机械变化如何影响心肌细胞动作潜力和电流动态.
- 探索基板刚度对Nav1.5表达和功能的影响.
- 阐明ECM沉积相关的心律失常的背后的机电机理.
主要方法:
- 人类和新生小鼠心肌细胞在可调节的3D聚二甲基 (PDMS) 基板上培养,模仿心脏梗塞脱细胞化ECM (dECM) 刚性.
- 基质的刚度在大约20-400kPa (Young的模量) 之间.
- 通过使用补丁记录评估了电生理学效应,并通过qPCR和免疫阻塞测试评估了基因/蛋白质表达.
主要成果:
- 基质刚度的增加逐渐降低了动作潜力 (AP) 的上升斜率,并诱导了前节律的AP形态.
- 电生理学分析显示了改变的通道动力学:电压依赖激活的向右转移和更快的关闭到不激活过渡.
- Nav1.5的表达和分布保持不变,这表明通道蛋白质的结构变化.
结论:
- 基质硬化会损害心肌细胞去极化,并通过Nav1.5功能障碍促进导电异常.
- 这项研究确定了一个关键的机电机制,将ECM沉积与心律失常联系起来.
- 研究结果表明,Nav1.5功能障碍是纤维化相关心律失常的关键因素.
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