Stretch‐induced reactive oxygen species contribute to the Frank-Starling mechanism
Stretch‐induced reactive oxygen species contribute to the Frank-Starling mechanism
复制标题
拉伸诱导的活性氧有助于 Frank-Starling 机制
DOI：
10.1113/jp284283
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Iribe Gentaro
中科院分区：
文献类型：
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作者：
Kaihara Keiko;Kai Hiroaki;Chiba Yumiko;Naruse Keiji;Iribe Gentaro
摘要心肌伸展会在生理上激活 NADPH 氧化酶 2 (NOX2)，从而增加活性氧 (ROS) 的产生。尽管已知生理学低水平 ROS 作为信号分子很重要，但拉伸诱导的 ROS 在完整心肌中的作用仍不清楚。为了解决这个问题，我们研究了拉伸诱导的 ROS 对 C57BL/6J 和 NOX2−/− 小鼠心肌细胞收缩力和钙瞬变的影响。使用附着在细胞两端的一对碳纤维对分离的心肌细胞进行轴向拉伸，以评估拉伸引起的收缩曲线和钙瞬变时间过程中的调节，并评估最大细胞弹性，这是细胞收缩性的指数，它是从收缩末期的力-长度关系获得的。在 NOX2−/− 小鼠中，峰值钙瞬变不会像野生型小鼠那样因拉伸而改变，但拉伸诱导的 ROS 的缺乏延迟了钙瞬变的上升并降低了收缩性。我们的数学模型研究表明，拉伸诱导的 ROS 增强了兰尼碱受体的激活，导致钙释放通量快速大幅增加，从而导致钙瞬变更快上升。钙瞬变幅度的轻微增加被ROS诱导的钙渗漏导致的肌浆网钙含量减少所抵消，但钙瞬变的更快上升仍然保持了较高的收缩性。总之，拉伸诱导的 ROS 的生理作用是增加收缩力以抵消给定的前负荷，也就是说，它有助于心脏的 Frank-Starling 定律。要点心肌拉伸增加了 NADPH 氧化酶 2 产生的活性氧。我们使用 NADPH 氧化酶 2 敲除小鼠来阐明拉伸诱导的活性氧在心脏中的生理作用。我们发现拉伸诱导的活性氧调节钙瞬变的上升阶段和增加心肌收缩力。数学模型模拟研究表明，活性氧快速激活兰尼碱受体对于增加收缩力非常重要。这种反应对心肌有利，因为心肌必须针对给定的预负荷进行收缩。
AbstractMyocardial stretch physiologically activates NADPH oxidase 2 (NOX2) to increase reactive oxygen species (ROS) production. Although physiological low‐level ROS are known to be important as signalling molecules, the role of stretch‐induced ROS in the intact myocardium remains unclear. To address this, we investigated the effects of stretch‐induced ROS on myocardial cellular contractility and calcium transients in C57BL/6J and NOX2−/−mice. Axial stretch was applied to the isolated cardiomyocytes using a pair of carbon fibres attached to both cell ends to evaluate stretch‐induced modulation in the time course of the contraction curve and calcium transient, as well as to evaluate maximum cellular elastance, an index of cellular contractility, which is obtained from the end‐systolic force–length relationship. In NOX2−/−mice, the peak calcium transient was not altered by stretch, as that in wild‐type mice, but the lack of stretch‐induced ROS delayed the rise of calcium transients and reduced contractility. Our mathematical modelling studies suggest that the augmented activation of ryanodine receptors by stretch‐induced ROS causes a rapid and large increase in the calcium release flux, resulting in a faster rise in the calcium transient. The slight increase in the magnitude of calcium transients is offset by a decrease in sarcoplasmic reticulum calcium content as a result of ROS‐induced calcium leakage, but the faster rise in calcium transients still maintains higher contractility. In conclusion, a physiological role of stretch‐induced ROS is to increase contractility to counteract a given preload, that is, it contributes to the Frank–Starling law of the heart.Key pointsMyocardial stretch increases the production of reactive oxygen species by NADPH oxidase 2.We used NADPH oxidase 2 knockout mice to elucidate the physiological role of stretch‐induced reactive oxygen species in the heart.We showed that stretch‐induced reactive oxygen species modulate the rising phase of calcium transients and increase myocardial contractility.A mathematical model simulation study demonstrated that rapid activation of ryanodine receptors by reactive oxygen species is important for increased contractility.This response is advantageous for the myocardium, which must contract against a given preload.