PDF(Pubmed)
Abstract：
The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic dysfunction led to new concepts regarding how levels of oxidative stress affect the heartbeat. Major sarcomere proteins for which there is evidence of S-glutathionylation include cardiac myosin binding protein C (cMyBP-C), actin, cardiac troponin I (cTnI) and titin. Our hypothesis is that these S-glutathionylated proteins are significant factors in acquired and familial disorders of the heart; and, when released into the serum, provide novel biomarkers. We consider the molecular mechanisms for these effects in the context of recent revelations of how these proteins control cardiac dynamics in close collaboration with Ca2+ fluxes. These revelations were made using powerful approaches and technologies that were focused on thin filaments, thick filaments, and titin filaments. Here we integrate their regulatory processes in the sarcomere as modulated mainly by neuro-humoral control of phosphorylation inasmuch evidence indicates that S-glutathionylation and protein phosphorylation, promoting increased dynamics and modifying the Frank-Starling relation, may be mutually exclusive. Earlier studies demonstrated that in addition to cTnI as a well-established biomarker for cardiac disorders, serum levels of cMyBP-C are also a biomarker for cardiac disorders. We describe recent studies approaching the question of whether serum levels of S-glutathionylated-cMyBP-C could be employed as an important clinical tool in patient stratification, early diagnosis in at risk patients before HFpEF, determination of progression, effectiveness of therapeutic approaches, and as a guide in developing future therapies.
摘要：
心脏肌节蛋白是S-谷胱甘肽酰化的底物，并且这种翻译后修饰与舒张功能障碍密切相关的发现导致了有关氧化应激水平如何影响心跳的新概念。有证据表明存在S-谷胱甘肽酰化的主要肌节蛋白包括心肌肌球蛋白结合蛋白C（cMyBP-C），肌动蛋白，心肌肌钙蛋白I（cTnI）和肌动蛋白。我们的假设是，这些S-谷胱甘肽酰化蛋白是心脏获得性和家族性疾病的重要因素；和，当释放到血清中时，提供新的生物标志物。我们在最近发现这些蛋白质如何与Ca2通量密切合作控制心脏动力学的背景下考虑了这些作用的分子机制。这些启示是使用强大的方法和技术，专注于细丝，粗丝,和提丁细丝。在这里，我们将它们的调节过程整合在肌节中，主要由磷酸化的神经体液控制调节，因为许多证据表明S-谷胱甘肽酰化和蛋白质磷酸化，促进增加的动力和修改弗兰克-斯塔林关系，可能是相互排斥的。早期的研究表明，除了cTnI作为一个公认的心脏疾病的生物标志物，cMyBP-C的血清水平也是心脏疾病的生物标志物。我们描述了最近的研究接近的问题，S-谷胱甘肽酰化-cMyBP-C的血清水平是否可以用作患者分层的重要临床工具，在HFpEF之前对高危患者进行早期诊断，进展的确定，治疗方法的有效性，并作为开发未来疗法的指南。
