S-glutathiolation of cardiac myosin-binding protein C in contractile dysfunction

收缩功能障碍中心肌肌球蛋白结合蛋白 C 的 S-谷胱甘肽化

• 批准号: 252120716
• 负责人: Professorin Dr. Friederike Cuello
• 金额: --
• 依托单位: Institut für Experimentelle Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/252120716?language=en
• 关键词: glutathiolation; cardiac; myosin; binding; protein

Heart failure (HF) is a clinical syndrome that arises from diverse causes and remains one of the leading factors of human mortality. Understanding the molecular mechanisms that govern cardiac function and their modifications during disease development is likely to identify key elements that might provide targets for novel treatment strategies. Cardiac myosin-binding protein C (cMyBP-C) is a thick filament-associated protein involved in the maintenance of sarcomere integrity and in the regulation of contraction and relaxation. Importantly, phosphorylation of cMyBP-C within the N-terminal M-domain leads to acceleration of cross-bridge cycling kinetics and force generation through removal of a structural constraint on myosin heads. Furthermore, phosphorylation has been described to protect myofilaments from enzymatic degradation under disease conditions, such as ischemia/reperfusion. We have obtained evidence that cMyBP-C is subject to oxidative post-translational modification, namely S-glutathiolation. We mapped one S-glutathiolation site within the C1-M-C2 domain of cMyBP-C to cysteine 249, in close vicinity to the phosphorylation-regulated M-domain. However, whether S-glutathiolation of cMyBP-C at Cys249 impacts on cardiac myocyte and whole heart function and the interplay and balance between phosphorylation and oxidation in health and disease warrants thorough investigation. Therefore, we propose (1) to explore the effect of S-glutathiolation on cMyBP-C function in vitro, (2) to elucidate a potential crosstalk between phosphorylation and oxidation and (3) to investigate the impact of S-glutathiolation on cMyBP-C function in vivo under (patho)physiological conditions. The project will lead to a better understanding of the molecular mechanisms underlying contractile dysfunction and may provide perspective to advance the development of novel treatment strategies.

心力衰竭（HF）是由多种原因引起的临床综合征，并且仍然是人类死亡的主要因素之一。了解在疾病发展过程中控制心脏功能及其修饰的分子机制可能会确定可能为新治疗策略提供靶点的关键因素。心肌肌球蛋白结合蛋白C（cMyBP-C）是一种与肌节完整性的维持及肌节收缩和舒张的调节有关的稠蛋白。重要的是，N-末端M-结构域内cMyBP-C的磷酸化导致跨桥循环动力学的加速和通过去除肌球蛋白头上的结构约束而产生的力。此外，磷酸化已被描述为保护肌丝在疾病条件下（例如缺血/再灌注）免于酶促降解。我们已经获得的证据表明，cMyBP-C是受氧化翻译后修饰，即S-谷胱甘肽。我们将cMyBP-C的C1-M-C2结构域内的一个S-谷胱甘肽化位点定位于半胱氨酸249，该位点紧邻磷酸化调节的M结构域。然而，cMyBP-C在Cys 249处的S-谷胱甘肽化是否影响心肌细胞和整个心脏功能以及健康和疾病中磷酸化和氧化之间的相互作用和平衡需要进行彻底的研究。因此，我们建议（1）在体外探索S-谷胱甘肽化对cMyBP-C功能的影响，（2）阐明磷酸化和氧化之间的潜在串扰，以及（3）在（病理）生理条件下研究S-谷胱甘肽化对cMyBP-C功能的体内影响。该项目将导致更好地了解收缩功能障碍的分子机制，并可能为推进新的治疗策略的发展提供视角。

项目成果

S‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure

Sâ 谷胱甘肽修饰会损害人心力衰竭中心肌肌球蛋白结合蛋白 C 的磷酸调节和功能

• DOI: 10.1096/fj.201500048
• 发表时间: 2016
• 期刊: The FASEB Journal
• 作者: Stathopoulou K;Wittig I;Heidler J;Piasecki A;Richter F;Diering S;van der Velden J;Buck F;Donzelli S;Schroeder E;Wijnker P;Voigt N;Dobrev D;Sadayappan S;Eschenhagen T;Carrier L;Eaton P;Cuello F
• 通讯作者: Cuello F

Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology.

• DOI: 10.1016/j.gene.2015.09.008
• 发表时间: 2015-12-01
• 期刊: Gene
• 影响因子: 3.5
• 作者: Carrier L;Mearini G;Stathopoulou K;Cuello F
• 通讯作者: Cuello F

Analysis of fibrosis in control or pressure overloaded rat hearts after mechanical unloading by heterotopic heart transplantation

• DOI: 10.1038/s41598-019-42263-1
• 发表时间: 2019-04
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: A. Schaefer;Y. Schneeberger;S. Schulz;S. Krasemann;Tessa R Werner;A. Piasecki;Grit Höppner;Christian Müller;Karoline Morhenn;K. Lorenz;D. Wieczorek;A. Schwoerer;T. Eschenhagen;H. Ehmke;H. Reichenspurner;J. Stenzig;F. Cuello