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核糖体测序分析揭示心肌肥厚中的保守翻译调控机制(英文)

王宝森^1,2,3,4, 吕舰^3,4,5, 詹宏潮³, 方宇^3,4, 郭秋晓^3,4, 王君梅³, 李佳洁³, 徐安琪^1,2,3,4, 马肖⁴, 郭宁宁^3,4,5, 李红^1,2, 王志华^3,4,*

¹广州中医药大学基础医学院生物化学与分子生物学系，广州510006；²广州中医药大学基础医学院中西医结合基础研究中心，广州 510006；³中国医学科学院阜外医院深圳医院深圳市心血管疾病重点实验室，深圳 518057；⁴中国医学科学院北京协和医学院阜外医院国家心血管病中心/心血管疾病全国重点实验室，北京 100037；⁵中国科学院深圳先进技术研究院，深圳 518055

摘要

病理性心肌肥厚的主要特征是由翻译活性增强导致的蛋白质过度合成。然而，心脏应激下翻译水平的调控机制仍不清楚。在本研究中，我们分析了由主动脉缩窄术(transaortic constriction, TAC)诱发的小鼠心肌肥厚模型中的翻译活性，联合人类扩张型心肌病(dilated cardiomyopathy, DCM)中的翻译组变化探索了翻译调控的保守性。结果显示，TAC后8 周心脏重量与体重比值显著增加，射血分数和缩短分数显著降低。嘌呤霉素(puromycin)掺入试验表明，TAC显著提高左心室的蛋白质合成速率。RNA测序揭示了1632 个差异表达基因，这些基因在包括细胞外基质重塑、代谢过程和与病理性心肌细胞生长相关的信号级联等通路中表现出功能富集。核糖体测序(Ribo-seq)分析结果显示，TAC后1495个基因翻译效率显著增强，933个基因翻译效率被显著抑制。相比之下，在DCM患者中，有1354 个基因翻译效率显著增强，1213 个基因翻译效率被显著抑制。尽管大部分发生翻译调控的基因在DCM患者和TAC 小鼠之间缺乏保守性，我们鉴定出包括Nos3、Kcnj8、Adcy4、Itpr1、Fasn、Scd1 等在内的93 个基因在小鼠和人类之间具有高度保守的翻译调控，这些基因与心肌功能、信号转导和能量代谢密切相关，尤其显著富集于cGMP-PKG信号转导和脂肪酸代谢通路。此外，在差异翻译效率基因的5′非翻译区中，通过基序分析发现了显著富集的、在人类DCM患者和TAC小鼠中显示出高度序列保守性的调控元件。该研究揭示了心肌肥厚在翻译水平上的调控新机制，并鉴定了保守的翻译敏感靶点，这些靶点在临床治疗心肌肥厚和心力衰竭方面具有潜在应用价值。

关键词： 心肌肥厚; 扩张型心肌病; 核糖体印迹测序; 转录组测序; 蛋白翻译效率

Conserved translational control in cardiac hypertrophy revealed by ribosome profiling

WANG Bao-Sen^1,2,3,4, LYU Jian^3,4,5, ZHAN Hong-Chao³, FANG Yu^3,4, GUO Qiu-Xiao^3,4, WANG Jun-Mei³, LI Jia-Jie³, XU An-Qi^1,2,3,4, MA Xiao⁴, GUO Ning-Ning^3,4,5, LI Hong^1,2, WANG Zhi-Hua^3,4,*

¹Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China；²The Research Center of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China；³Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Shenzhen Hospital, Chinese Academy of Medical Sciences, Shenzhen 518057, China；⁴State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China；⁵Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China

Abstract

A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity. However, regulatory mechanisms at the translational level under cardiac stress remain poorly understood. Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction (TAC) and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy (DCM). The results showed that the heart weight to body weight ratio was significantly elevated, and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC. Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle. RNAseq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling, metabolic processes, and signaling cascades associated with pathological cardiomyocyte growth. When combined with ribosome profiling analysis, we revealed that translation efficiency (TE) of 1,495 genes was enhanced, while the TE of 933 genes was inhibited following TAC. In DCM patients, 1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level. Although the majority of the genes were not shared between mouse and human, we identified 93 genes, including Nos3, Kcnj8, Adcy4, Itpr1, Fasn, Scd1, etc., with highly conserved translational regulations. These genes were remarkably associated with myocardial function, signal transduction, and energy metabolism, particularly related to cGMP-PKG signaling and fatty acid metabolism. Motif analysis revealed enriched regulatory elements in the 5′ untranslated regions (5′UTRs) of transcripts with differential TE, which exhibited strong cross-species sequence conservation. Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.

Key words: Cardiac hypertrophy; dilated cardiomyopathy; Ribo-seq; RNA-seq; translation efficiency

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通讯作者：王志华　　E-mail:

DOI: 10.13294/j.aps.2025.0077

引用本文：

王宝森, 吕舰, 詹宏潮, 方宇, 郭秋晓, 王君梅, 李佳洁, 徐安琪, 马肖, 郭宁宁, 李红, 王志华. 核糖体测序分析揭示心肌肥厚中的保守翻译调控机制(英文)[J]. 生理学报 2025; 77 (5): 757-774.

WANG Bao-Sen, LYU Jian, ZHAN Hong-Chao, FANG Yu, GUO Qiu-Xiao, WANG Jun-Mei, LI Jia-Jie, XU An-Qi, MA Xiao, GUO Ning-Ning, LI Hong, WANG Zhi-Hua. Conserved translational control in cardiac hypertrophy revealed by ribosome profiling. Acta Physiol Sin 2025; 77 (5): 757-774