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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

Received: 　　Accepted:

Corresponding author: 王志华　　E-mail:

DOI: 10.13294/j.aps.2025.0077

Citing This Article：

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