Mechanoelectric coupling and arrhythmogenesis in cardiomyocytes contracting under mechanical afterload in a 3D viscoelastic hydrogel.
Mechanoelectric coupling and arrhythmogenesis in cardiomyocytes contracting under mechanical afterload in a 3D viscoelastic hydrogel.
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DOI：
10.1073/pnas.2108484118
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发表时间：
2021-08-03
影响因子：
11.1
通讯作者：
Chen-Izu Y
中科院分区：
文献类型：
--
作者：
Hegyi B;Shimkunas R;Jian Z;Izu LT;Bers DM;Chen-Izu Y
当泵送血液对抗血管阻力产生的机械后负荷时，心脏会自动调节其收缩强度以维持心输出量。心血管疾病后负荷增加与心律失常有关。然而，根本的机制仍然难以捉摸。在这里，我们通过将单个心肌细胞嵌入三维粘弹性水凝胶中以在细胞收缩期间施加后负荷来研究后负荷对电生理的影响。我们发现后负荷通过一氧化氮合酶1（NOS 1）信号转导来调节多个离子通道，以延长动作电位，增加Ca 2+瞬变，并增强收缩性。然而，更高的后负荷导致不协调的交替，这是致瘤的。因此，我们的研究结果揭示了后负荷诱导的机械-化学-电-转导通路，其关闭心脏兴奋-收缩耦合中的反馈回路以实现收缩性的自动调节。心脏泵送血液对抗来自动脉阻力的机械后负荷，后负荷增加可能改变心脏电生理学并导致危及生命的心律失常。然而，心肌细胞中机械电耦合的细胞和分子机制仍不清楚。我们开发了一种创新的膜片钳凝胶技术，将心肌细胞嵌入三维（3D）粘弹性水凝胶中，该水凝胶在常规的心肌细胞收缩期间施加后负荷。在这里，我们研究了后负荷如何影响动作电位，离子电流，细胞内Ca 2+瞬变，和成年兔心室心肌细胞的细胞收缩。结果发现，后负荷使动作电位时程（APD）延长，瞬时外向钾电流增加，内向整流钾电流减少，L型钙电流增加。Ca 2+内流增加引起Ca 2+瞬变和收缩性增强。此外，后负荷升高导致APD和Ca 2+瞬变的不协调交替。在动作电位钳制下，Ca ~（2+）交替持续存在，表明交替是Ca ~（2+）依赖的。此外，通过抑制一氧化氮合酶1（NOS 1），所有这些后负荷效应均显著减弱。总之，我们的数据揭示了一个机械-化学-电转导（MCET）机制，通过NOS 1-一氧化氮信号传导急性转导后负荷，调节动作电位，Ca 2+瞬变，和收缩性。MCET通路在兴奋-Ca 2+信号传导-收缩偶联中提供反馈回路，使得能够响应于后负荷而自动调节心肌细胞中的收缩性。这种MCET机制是个体心肌细胞（以及心脏）的组成部分，以内在地增强其收缩力，以响应其必须工作的负荷。虽然这种MCET在很大程度上是对生理负荷变化的补偿，但它也可能在过度病理负荷下增加对心律失常的易感性。
The heart autoregulates its contractile strength to maintain cardiac output when pumping blood against the mechanical afterload from vascular resistance. Increased afterload in cardiovascular diseases is associated with cardiac arrhythmias. However, the underlying mechanisms remain elusive. Here, we studied the afterload effect on electrophysiology by embedding single cardiomyocytes in a three-dimensional viscoelastic hydrogel to apply afterload during cell contraction. We found that afterload is acutely transduced via nitric oxide synthase 1 (NOS1) signaling to modulate multiple ion channels to prolong action potential, increase Ca2+ transient, and enhance contractility. However, higher afterload causes a discordant alternans that is arrhythmogenic. Hence, our findings reveal an afterload-induced mechano-chemo-electro-transduction pathway that closes feedback loops in cardiac excitation–contraction coupling to enable autoregulation of contractility. The heart pumps blood against the mechanical afterload from arterial resistance, and increased afterload may alter cardiac electrophysiology and contribute to life-threatening arrhythmias. However, the cellular and molecular mechanisms underlying mechanoelectric coupling in cardiomyocytes remain unclear. We developed an innovative patch-clamp-in-gel technology to embed cardiomyocytes in a three-dimensional (3D) viscoelastic hydrogel that imposes an afterload during regular myocyte contraction. Here, we investigated how afterload affects action potentials, ionic currents, intracellular Ca2+ transients, and cell contraction of adult rabbit ventricular cardiomyocytes. We found that afterload prolonged action potential duration (APD), increased transient outward K+ current, decreased inward rectifier K+ current, and increased L-type Ca2+ current. Increased Ca2+ entry caused enhanced Ca2+ transients and contractility. Moreover, elevated afterload led to discordant alternans in APD and Ca2+ transient. Ca2+ alternans persisted under action potential clamp, indicating that the alternans was Ca2+ dependent. Furthermore, all these afterload effects were significantly attenuated by inhibiting nitric oxide synthase 1 (NOS1). Taken together, our data reveal a mechano-chemo-electrotransduction (MCET) mechanism that acutely transduces afterload through NOS1–nitric oxide signaling to modulate the action potential, Ca2+ transient, and contractility. The MCET pathway provides a feedback loop in excitation–Ca2+ signaling–contraction coupling, enabling autoregulation of contractility in cardiomyocytes in response to afterload. This MCET mechanism is integral to the individual cardiomyocyte (and thus the heart) to intrinsically enhance its contractility in response to the load against which it has to do work. While this MCET is largely compensatory for physiological load changes, it may also increase susceptibility to arrhythmias under excessive pathological loading.
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影响因子：
7.3
作者：
Jian Z;Han H;Zhang T;Puglisi J;Izu LT;Shaw JA;Onofiok E;Erickson JR;Chen YJ;Horvath B;Shimkunas R;Xiao W;Li Y;Pan T;Chan J;Banyasz T;Tardiff JC;Chiamvimonvat N;Bers DM;Lam KS;Chen-Izu Y
通讯作者：
Chen-Izu Y
影响因子：
5.5
作者：
Fedorov, Vadim V.;Lozinsky, Ilya T.;Efimov, Igor R.
通讯作者：
Efimov, Igor R.
影响因子：
8.4
作者：
Hegyi, Bence;Morotti, Stefano;Bers, Donald M.
通讯作者：
Bers, Donald M.
DOI：
10.1073/pnas.1718211115
发表时间：
2018-03-27
影响因子：
11.1
作者：
Hegyi, Bence;Bossuyt, Julie;Chen-Izu, Ye
通讯作者：
Chen-Izu, Ye
DOI：
10.3390/life11060503
发表时间：
2021-05-29
期刊：
Life (Basel, Switzerland)
影响因子：
--
作者：
Izu L;Shimkunas R;Jian Z;Hegyi B;Kazemi-Lari M;Baker A;Shaw J;Banyasz T;Chen-Izu Y
通讯作者：
Chen-Izu Y