title: The histone acetyltransferase MOF overexpression blunts cardiac hypertrophy by targeting ROS in mice.
abstract: Imbalance between histone acetylation/deacetylation critically participates in the expression of hypertrophic fetal genes and development of cardiac hypertrophy. While histone deacetylases play dual roles in hypertrophy, current evidence reveals that histone acetyltransferase such as p300 and PCAF act as pro-hypertrophic factors. However, it remains elusive whether some histone acetyltransferases can prevent the development of hypertrophy. Males absent on the first (MOF) is a histone acetyltransferase belonging to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. Here in this study, we reported that MOF expression was down-regulated in failing human hearts and hypertrophic murine hearts at protein and mRNA levels. To evaluate the roles of MOF in cardiac hypertrophy, we generated cardiac-specific MOF transgenic mice. MOF transgenic mice did not show any differences from their wide-type littermates at baseline. However, cardiac-specific MOF overexpression protected mice from transverse aortic constriction (TAC)-induced cardiac hypertrophy, with reduced radios of heart weight (HW)/body weight (BW), lung weight/BW and HW/tibia length, decreased left ventricular wall thickness and increased fractional shortening. We also observed lower expression of hypertrophic fetal genes in TAC-challenged MOF transgenic mice compared with that of wide-type mice. Mechanically, MOF overexpression increased the expression of Catalase and MnSOD, which blocked TAC-induced ROS and ROS downstream c-Raf-MEK-ERK pathway that promotes hypertrophy. Taken together, our findings identify a novel anti-hypertrophic role of MOF, and MOF is the first reported anti-hypertrophic histone acetyltransferase.
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, PR China. Electronic address: qiaolab@126.com.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, PR China.
authors.forename: Weili
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, PR China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Gai
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, PR China.
authors.forename: Juexin
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; C000622683:Kat8 protein, mouse
keywords: Cardiac hypertrophy; Histone acetyltransferase; MOF; ROS