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1. NAP1L5 Promotes Nucleolar Hypertrophy and Is Required for Translation Activation During Cardiomyocyte Hypertrophy

Author

Ningning Guo, Di Zheng, Jiaxin Sun, Jian Lv, Shun Wang, Yu Fang, Zhenyi Zhao, Sai Zeng, Qiuxiao Guo, Jingjing Tong, and Zhihua Wang

Subjects
cardiomyocyte hypertrophy, NAP1L5, translation control, nucleolar hypertrophy, ribosome assembly, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Pathological growth of cardiomyocytes during hypertrophy is characterized by excess protein synthesis; however, the regulatory mechanism remains largely unknown. Using a neonatal rat ventricular myocytes (NRVMs) model, here we find that the expression of nucleosome assembly protein 1 like 5 (Nap1l5) is upregulated in phenylephrine (PE)-induced hypertrophy. Knockdown of Nap1l5 expression by siRNA significantly blocks cell size enlargement and pathological gene induction after PE treatment. In contrast, Adenovirus-mediated Nap1l5 overexpression significantly aggravates the pro-hypertrophic effects of PE on NRVMs. RNA-seq analysis reveals that Nap1l5 knockdown reverses the pro-hypertrophic transcriptome reprogramming after PE treatment. Whereas, immune response is dominantly enriched in the upregulated genes, oxidative phosphorylation, cardiac muscle contraction and ribosome-related pathways are remarkably enriched in the down-regulated genes. Although Nap1l5-mediated gene regulation is correlated with PRC2 and PRC1, Nap1l5 does not directly alter the levels of global histone methylations at K4, K9, K27 or K36. However, puromycin incorporation assay shows that Nap1l5 is both necessary and sufficient to promote protein synthesis in cardiomyocyte hypertrophy. This is attributable to a direct regulation of nucleolus hypertrophy and subsequent ribosome assembly. Our findings demonstrate a previously unrecognized role of Nap1l5 in translation control during cardiac hypertrophy.

Published
2021
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2. Dose-dependent Effects of PRC2 and HDAC Inhibitors on Cardiomyocyte Hypertrophy Induced by Phenylephrine

Author

Zhihua Wang, Weixin Chen, Zhenyi Zhao, Jian Lv, Ningning Guo, Qiuxiao Guo, Sai Zeng, and Yu Fang

Subjects
Pharmacology, Clinical Biochemistry, Drug Discovery, Molecular Medicine
Abstract

aims: To elucidate the roles of PRC2 and HDACs in cardiomyocyte hypertrophy. background: Postnatal cardiomyocytes respond to stress signals by hypertrophic growth and fetal gene reprogramming, which involves epigenetic remodeling mediated by histone methyltransferase polycomb repressive complex 2 (PRC2) and histone deacetylases (HDACs). However, it remains unclear to what extent these histone modifiers contribute to the development of cardiomyocyte hypertrophy. objective: To compare the dose-dependent effects of GSK126 and TSA, inhibitors of PRC2 and HDACs, respectively, on cardiomyocyte hypertrophy. method: Neonatal rat ventricular myocytes (NRVMs) were stimulated by phenylephrine (PE; 50μM) to induce hypertrophy in the presence or absence of the PRC2 inhibitor GSK126 or the HDACs inhibitor Trichostatin A (TSA). Histone methylation and acetylation were measured by Western blot. Cell size was determined by wheat germ agglutinin (WGA) staining. Cardiac hypertrophy markers were quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). result: PE treatment induced the expression of cardiac hypertrophy markers, including natriuretic peptide A (Nppa), natriuretic peptide B (Nppb), and myosin heavy chain 7 (Myh7), in a time-dependent manner in NRVMs. Histone modifications, including H3K27me3, H3K9ac, and H3K27ac, were dynamically altered after PE treatment. Treatment with TSA and GSK126 dose-dependently repressed histone acetylation and methylation, respectively. Whereas TSA reversed the PE-induced cell size enlargement in a wide range of concentrations, cardiomyocyte hypertrophy was only inhibited by GSK126 at a higher dose (1μM). Consistently, TSA dose-dependently suppressed the induction of Nppa, Nppb, and Myh7/Myh6 ratio, while these indexes were only inhibited by GSK126 at 1μM. However, TSA, but not GSK126, caused pro-hypertrophic expression of pathological genes at the basal level. conclusion: Our data demonstrate diversified effects of TSA and GSK126 on PE-induced cardiomyocyte hypertrophy, and shed a light on the epigenetic reprogramming in the pathogenesis of cardiac hypertrophy. other: Our data systematically compared the effects of TSA and GSK126 on PE-induced cardiomyocyte hypertrophy, and demonstrate the concentration thresholds for their protective function.

Published
2023

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