肌内细胞骨架蛋白在左心室舒张功能障碍机制中的作用:重点关注titin

IF 0.2 Q4 MEDICINE, GENERAL & INTERNAL
V. V. Kalyuzhin, A. T. Teplyakov, I. D. Bespalova, E. V. Kalyuzhina, G. E. Chernogoryuk, N. N. Terentyeva, E. V. Grakova, K. V. Kopeva, V. Yu. Usov, N. P. Garganeeva, I. K. Livshits, I. V. Petrova, T. V. Lasukova
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引用次数: 0

摘要

认识到孤立性左室舒张功能障碍(DD)在所有心力衰竭病例中约占50%,需要深入了解其主要机制,以便制定有效的诊断和治疗策略。尽管对DD的机制有丰富的认识,但关于舒张的病理生理的许多重要问题仍未解决。特别是,肌内细胞骨架病理在所谓的主动(舒张开始时左室心肌松弛和房室压力梯度,与健康心脏密切相关)和被动(心肌僵硬)舒张特征恶化中的作用需要澄清。讲座简要讨论了DD机制的复杂层次(从肌节到整个心脏),并涵盖了巨蛋白titin在后者中的作用,后者是细胞内硬度的主要决定因素。在多种病理条件下(压力过载、缺血、炎症、心脏毒性作用、氧化应激等),DD的心肌舒张损伤和壁顺性恶化可以通过titin表达向更严格的N2B亚型转移、蛋白激酶a和G的低磷酸化或丝氨酸/苏氨酸磷酸酶5在包含独特N2B序列的可扩展蛋白片段中的分子去磷酸化来解释。蛋白激酶C对titin的PEVK区域的过度磷酸化,以及ca2 +依赖性的titin - actin相互作用的抑制。破译这些机制的结果一方面可以成为开发目前没有有效治疗方法的舒张性心力衰竭靶向治疗新方法的工具,另一方面也是了解已经用于治疗左室射血分数保留的慢性心力衰竭的药物治疗效果的关键。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The role of endosarcomeric cytoskeleton proteins in the mechanisms of left ventricular diastolic dysfunction: focus on titin
Recognizing the fact that isolated left ventricular (LV) diastolic dysfunction (DD) underlies approximately 50% of all heart failure cases requires a deep understanding of its principal mechanisms so that effective diagnostic and treatment strategies can be developed. Despite abundance of knowledge about the mechanisms underlying DD, many important questions regarding the pathophysiology of diastole remain unresolved. In particular, the role of endosarcomeric cytoskeleton pathology in the deterioration of the so-called active (relaxation of the LV myocardium and the atrioventricular pressure gradient at the beginning of diastole, closely related to it in a healthy heart) and passive (myocardial stiffness) characteristics of diastole needs to be clarified. The lecture briefly discusses the complex hierarchy of DD mechanisms (from the sarcomere to the whole heart) and covers the role of the giant protein titin in the latter, which is the main determinant of intracellular stiffness. Impairment of myocardial relaxation and deterioration of its wall compliance under a wide range of pathological conditions (pressure overload, ischemia, inflammation, cardiotoxic effects, oxidative stress, etc.) underlying DD can be explained by a shift in titin expression toward its more rigid N2B isoform, hypophosphorylation by protein kinases A and G or dephosphorylation by serine / threonine phosphatase 5 of its molecule in the extensible protein segment containing a unique N2B sequence, hyperphosphorylation of PEVK regions of titin by protein kinase C, as well as inhibition of the Ca 2 +-dependent titin – actin interaction. The results of deciphering these mechanisms can become a tool for developing new approaches to targeted therapy for diastolic heart failure that currently does not have effective treatment, on the one hand, and the key to understanding the therapeutic effects of drugs already used to treat chronic heart failure with preserved LV ejection fraction, on the other hand.
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来源期刊
Byulleten Sibirskoy Meditsiny
Byulleten Sibirskoy Meditsiny MEDICINE, GENERAL & INTERNAL-
CiteScore
0.70
自引率
50.00%
发文量
102
审稿时长
8 weeks
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