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  • br Acknowledgments This work was supported by the National

    2022-06-18


    Acknowledgments This work was supported by the National Natural Science Foundation of China DMOG sale (31100111), the Nature Science Research Project of Anhui Province (1508085MC43), the subject construction project from Anhui Academy of Agricultural Sciences (14A1110). We would like to acknowledge the technical support of Dr B Tyler. We would also like to thank Dr IT Riley for advice during preparation of the manuscript.
    Introduction Presently, heart failure has been one of the leading causes of morbidity and mortality worldwide. Cardiac hypertrophy is one of the most important pathological bases of heart failure [1]. Cardiac hypertrophy is a common response of cardiomyocytes to physiology and pathological stimuli. Because mammalian cardiomyocytes fail to divide soon after birth, hypertrophy is the only way for them to response to the increased workload. During cardiac hypertrophy, not only the cell size is increased in cardiomyocytes, but the sarcomeres are added and reorganized, and a group of genes that are usually expressed during fetal heart development are re-expressed. These alterations are compensatory system of the heats initially to deal with the increased workload on the heart. However, sustained hypertrophy would result in congestive heart failure and sudden death due to arrhythmias [1], [2]. At the molecular level, hypertrophy of cardiomyocytes is an outcome of imbalance between pro-hypertrophic and anti-hypertrophic factors and their downstream mechanisms controlling cell growth [2]. Accumulating studies have revealed a key role of histone acetyltransferases (HATs) and deacetylases (HDACs) in the controlling of cardiac hypertrophy. HDACs of different DMOG sale have been shown to have different effects on cardiac growth. HDAC2 of the class I HDAC regulates expression of many fetal cardiac isoforms. HDAC2 deficiency or chemical HDAC inhibition prevented the re-expression of fetal genes in hearts and attenuated cardiac hypertrophy when exposed to hypertrophic stimuli [3]. In contrast, class IIa HDACs, such as HDAC5 and HDAC9, function as signal-responsive repressors of cardiac hypertrophy by inactivating MEF2 [4], [5], [6]. For the NAD+-dependent class III HDAC or the Sirtuin family, although the role of SIRT1 in cardiac hypertrophy is under debate [7], [8], SIRT3, SIRT6 and SIRT7 are revealed to be anti-hypertrophic factors [9], [10], [11]. The HATs have five families, among which, p300 and PCAF of the GNAT family are reported to be pro-hypertrophic factors [12], [13]. However, the role of other HATs in hypertrophic cardiopathy still remains elusive. Males absent on the first (MOF) is a member of the MYST (MOS, KB2/Sas3, Sas2 and TIP60) family of histone acetyltransferase (HAT), and it was first described in Drosophila melanogaster as an essential component of the X-chromosome dosage compensation of male-specific lethal (MSL) complex [14], [15]. MOF is conserved among higher eukaryotes. H4K16 acetylation in higher eukaryotes is mainly carried out by MOF [16]. The function of MOF in dosage compensation is mediated by its acetyltransferase activity, which is tightly regulated by the MSL protein [15], [17]. Compared to the functions in Drosophila dosage compensation, the roles of MOF in mammals are less well characterized. Here in this study, we found that expression level of MOF decreased in human failing and murine hypertrophic hearts. Moreover, overexpression of MOF in mouse hearts blunted cardiac hypertrophy by targeting ROS and its downstream c-Raf-MEK-ERK pathway that facilitates hypertrophy.
    Materials and methods
    Results
    Discussion Here in this study, we firstly found the down-regulation of MOF in human failing and murine hypertrophic hearts. Further, we demonstrated that MOF blunted cardiac hypertrophy by targeting ROS and its downstream c-Raf-MEK-ERK pathway using a MOF transgenic mouse model (Fig. 4F). MOF is conserved among higher eukaryotes. In mammals, MOF is ubiquitously expressed and is clearly targeted to all chromosomes. Loss of MOF gene in mice causes peri-implantation lethality, as a result of massive disruption of chromatin architecture in a wide range of cells [19], [20]. In addition, MOF is important for ATM-dependent cell-cycle checkpoint control [21], and transcription activation of Hox genes in coordination with the H3K4 methyltransferase MLL [22], by maintaining normal chromatin structure. Loss of MOF leads to severe G2/M cell cycle arrest, massive chromosome aberration, and defects in ionizing radiation-induced DNA damage repair by both non-homologous end-joining and homologous recombination [23], [24]. All those effects are mediated by the acetylation activity of MOF on H4K16. However, the physiological and pathological function of MOF remains unknown. Here we identified a novel function of MOF in hypertrophic cardiopathy.