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

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.

Nucleosome assembly protein 1-like 5 alleviates Alzheimer’s disease-like pathological characteristics in a cell model

“…As one of the members of the NAP1L protein family, NAP1L5 was identified as an imprinted gene in human liver malignancy and congenital heart diseases and an important regulator of translation activation during cardiomyocyte hypertrophy ( Harada et al, 2002 ; Chang et al, 2021 ; Guo et al, 2021 ). However, the role of NAP1L5 in various diseases, including AD, remains largely unknown.…”

“…NAP1L5, first identified in the human liver malignancy as an imprinted gene, was also found to be hypomethylated in congenital heart diseases ( Harada et al, 2002 ; Smith et al, 2003 ; Chang et al, 2021 ). Recently, Wang et al showed that NAP1L5 promoted nucleolar hypertrophy during cardiomyocyte hypertrophy by regulating translation activation ( Guo et al, 2021 ). However, the role of NAP1L5 in AD remains largely unknown.…”

Carnosic acid protects against doxorubicin-induced cardiotoxicity through enhancing the Nrf2/HO-1 pathway

“…After 24 h of culture, the medium was changed to DMEM medium with 1% insulin-transferrin-selenium (ITS) (Invitrogen, USA) for another 24 h before further treatment. 16…”

“…After 24 h of culture, the medium was changed to DMEM medium with 1% insulin-transferrin-selenium (ITS) (Invitrogen, USA) for another 24 h before further treatment. 16 To induce DOX-related injury, the cells were starved overnight in DMEM containing 0.5% FBS and then incubated with DOX (1 μmol L −1 ) for 24 h. 8 The cells were pretreated with different concentrations of CA (0, 10, 20, 30, 40 μmol L −1 ) six hours before DOX administration. To knock down Nrf2 in cardiomyocytes, NRVMs were then transfected with 50 nM siRNA against Nrf2 or scrambled duplex with Lipofectamine 3000 (Invitrogen, USA) according to the manufacturer's instructions and then maintained in normal medium for additional 24 h before further stimulation according to our previous studies.…”

SLC25A26-mediated SAM compartmentalization coordinates translation and bioenergetics during cardiac hypertrophy

“…9 Pathological cardiac hypertrophy is characterized by enlarged cardiomyocyte size and excess protein synthesis. [10][11][12] Despite early indications of increased ribosome biogenesis, [13][14][15] little headway has been made in understanding the regulatory mechanisms governing translational control during cardiac hypertrophy. 16 While gene abnormalities in cardiac hypertrophy have been extensively examined at the transcriptional level, it is important to note that the cardiac translatome cannot be precisely dictated by the transcriptome due to ribosome efficacy and mRNA selectivity.…”