Chronic Activation of Tubulin Tyrosination Improves Heart Function.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Circulation research Pub Date : 2024-10-11 Epub Date: 2024-09-16 DOI:10.1161/CIRCRESAHA.124.324387
Niels Pietsch, Christina Y Chen, Svenja Kupsch, Lucas Bacmeister, Birgit Geertz, Marisol Herrera-Rivero, Bente Siebels, Hannah Voß, Elisabeth Krämer, Ingke Braren, Dirk Westermann, Hartmut Schlüter, Giulia Mearini, Saskia Schlossarek, Jolanda van der Velden, Matthew A Caporizzo, Diana Lindner, Benjamin L Prosser, Lucie Carrier
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引用次数: 0

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with the findings that microtubule detyrosination (dTyr-MT) is markedly elevated in heart failure. Acute reduction of dTyr-MT by inhibition of the detyrosinase (VASH [vasohibin]/SVBP [small VASH-binding protein] complex) or activation of the tyrosinase (TTL [tubulin tyrosine ligase]) markedly improved contractility and reduced stiffness in human failing cardiomyocytes and thus posed a new perspective for HCM treatment. In this study, we tested the impact of chronic tubulin tyrosination in an HCM mouse model (Mybpc3 knock-in), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs).

Methods: Adeno-associated virus serotype 9-mediated TTL transfer was applied in neonatal wild-type rodents, in 3-week-old knock-in mice, and in HCM human induced pluripotent stem cell-derived cardiomyocytes.

Results: We show (1) TTL for 6 weeks dose dependently reduced dTyr-MT and improved contractility without affecting cytosolic calcium transients in wild-type cardiomyocytes; (2) TTL for 12 weeks reduced the abundance of dTyr-MT in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in knock-in mice; (3) TTL for 10 days normalized cell area in HCM human induced pluripotent stem cell-derived cardiomyocytes; (4) TTL overexpression activated transcription of tubulins and other cytoskeleton components but did not significantly impact the proteome in knock-in mice; (5) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and wild-type EHTs. RNA sequencing and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-deficient versus TTL-deficient EHTs.

Conclusions: This study provides the first proof of concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the nonsarcomeric cytoskeleton in heart disease.

管蛋白酪氨酸化的慢性激活可改善心脏功能
理由:肥厚型心肌病(HCM)是由肉瘤基因变异引起的最常见的心脏遗传疾病,与左心室肥大和舒张功能障碍有关。最近,随着微管脱酪氨酸化(dTyr-MT)在心力衰竭中明显升高的发现,微管网络的作用引起了人们的兴趣。通过抑制脱酪氨酸酶(VASH[血管抑制素]/SVBP[小 VASH 结合蛋白]复合物)或激活酪氨酸酶(TTL[微管蛋白酪氨酸连接酶])来急性减少 dTyr-MT,可明显改善人类衰竭心肌细胞的收缩能力并降低僵硬度,从而为 HCM 治疗提供了新的视角:在这项研究中,我们测试了慢性小管蛋白酪氨酸化对 HCM 小鼠模型(Mybpc3 基因敲入)、人类 HCM 心肌细胞以及 SVBP 缺陷人类工程心脏组织(EHTs)的影响:在新生野生型啮齿类动物、3 周大的基因敲入小鼠和 HCM 人类诱导多能干细胞衍生心肌细胞中应用了腺相关病毒血清型 9 介导的 TTL 转移。我们发现:(1)TTL 6 周剂量依赖性地减少了野生型心肌细胞中的 dTyr-MT,并改善了收缩力,而不影响细胞钙瞬态;(2)TTL 12 周减少了基因敲入小鼠心肌中 dTyr-MT 的丰度,改善了舒张充盈、顺应性、心输出量和搏出量;(3) TTL 10 天能使 HCM 人诱导多能干细胞衍生心肌细胞的细胞面积正常化;(4) TTL 过表达能激活小管蛋白和其他细胞骨架成分的转录,但不会对基因敲入小鼠的蛋白质组产生显著影响;(5) 与 TTL 缺失型和野生型 EHT 相比,SVBP 缺失型 EHT 的 dTyr-MT 含量降低,力更大,松弛更快。RNA测序和质谱分析表明,SVBP缺陷型和TTL缺陷型EHT的心肌细胞成分和通路截然不同:这项研究首次证明了在 HCM 小鼠和人类 EHTs 中慢性激活微管蛋白酪氨酸化能改善心脏功能的概念,并为针对心脏病的非星形细胞骨架带来了希望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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