Stress-induced protein S-glutathionylation and phosphorylation crosstalk in cardiac sarcomeric proteins - Impact on heart function
Stress-induced protein S-glutathionylation and phosphorylation crosstalk in cardiac sarcomeric proteins - Impact on heart function
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DOI：
10.1016/j.ijcard.2017.12.004
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发表时间：
2018-05-01
影响因子：
3.5
通讯作者：
Cazorla, Olivier
中科院分区：
文献类型：
--
作者：
Chakouri, Nourdine;Reboul, Cyril;Cazorla, Olivier
背景资料：氧化应激和其他信号通路在心脏应激时收缩机制调节中的相互作用及其对心脏功能的影响仍然知之甚少。我们评估了β-肾上腺素能和氧化还原信号之间的串扰对肌节调节蛋白，肌球蛋白结合蛋白-C（MyBP-C）和肌钙蛋白I（TnI）的翻译后修饰的影响。方法和结果：我们模仿在体外高水平的生理心脏应激，迫使大鼠心脏产生高水平的氧化型谷胱甘肽。这导致MyBP-C S-谷胱甘肽化，与MyBP-C和TnI的较低蛋白激酶A（PKA）依赖性磷酸化相关，增加肌丝Ca 2+敏感性，以及降低离体灌注心脏的收缩和舒张特性。（运动诱导的低应激，LSE）增加了TnI和cMyBP-C磷酸化，并改善了体内（超声心动图）和离体（离体灌注心脏）的心脏功能。高应力引起的运动（HSE）改变强烈的氧化应激标志物和磷酸化没有改变，尽管PKA活性增加。HSE导致与肌丝Ca 2+敏感性缺陷相关的体内固有心功能障碍。为了限制HSE后蛋白质S-谷胱甘肽化，我们用N-乙酰半胱氨酸（NAC）处理大鼠。NAC恢复PKA调节肌丝Ca 2+敏感性的能力，并防止在HSE animals.Conclusion：在心脏应激下，肾上腺素能和氧化信号通路协同工作，改变肌丝特性，是心脏功能的关键调节因子。(C)2017爱思唯尔B. V.保留所有权利。
Background: The interplay between oxidative stress and other signaling pathways in the contractile machinery regulation during cardiac stress and its consequences on cardiac function remains poorly understood. We evaluated the effect of the crosstalk between beta-adrenergic and redox signaling on post-translational modifications of sarcomeric regulatory proteins, Myosin Binding Protein-C (MyBP-C) and Troponin I (TnI).Methods and results: We mimicked in vitro high level of physiological cardiac stress by forcing rat hearts to produce high levels of oxidized glutathione. This led to MyBP-C S-glutathionylation associated with lower protein kinase A (PKA) dependent phosphorylations of MyBP-C and TnI, increased myofilament Ca2+ sensitivity, and decreased systolic and diastolic properties of the isolated perfused heart Moderate physiological cardiac stress achieved in vivo with a single 35 min exercise (Low stress induced by exercise, LSE) increased TnI and cMyBP-C phosphorylations and improved cardiac function in vivo (echocardiography) and ex-vivo (isolated perfused heart). High stress induced by exercise (HSE) altered strongly oxidative stress markers and phosphorylations were unchanged despite increased PKA activity. HSE led to in vivo intrinsic cardiac dysfunction associated with myofilament Ca2+ sensitivity defects. To limit protein S-glutathionylation after HSE, we treated rats with N-acetylcysteine (NAC). NAC restored the ability of PKA to modulate myofilament Ca2+ sensitivity and prevented cardiac dysfunction observed in HSE animals.Conclusion: Under cardiac stress, adrenergic and oxidative signaling pathways work in concert to alter myofilament properties and are key regulators of cardiac function. (C) 2017 Elsevier B.V. All rights reserved.