title: GATA4 regulates Fgf16 to promote heart repair after injury.
abstract: Although the mammalian heart can regenerate during the neonatal stage, this endogenous regenerative capacity is lost with age. Importantly, replication of cardiomyocytes has been found to be the key mechanism responsible for neonatal cardiac regeneration. Unraveling the transcriptional regulatory network for inducing cardiomyocyte replication will, therefore, be crucial for the development of novel therapies to drive cardiac repair after injury. Here, we investigated whether the key cardiac transcription factor GATA4 is required for neonatal mouse heart regeneration. Using the neonatal mouse heart cryoinjury and apical resection models with an inducible loss of GATA4 specifically in cardiomyocytes, we found severely depressed ventricular function in the Gata4-ablated mice (mutant) after injury. This was accompanied by reduced cardiomyocyte replication. In addition, the mutant hearts displayed impaired coronary angiogenesis and increased hypertrophy and fibrosis after injury. Mechanistically, we found that the paracrine factor FGF16 was significantly reduced in the mutant hearts after injury compared with littermate controls and was directly regulated by GATA4. Cardiac-specific overexpression of FGF16 via adeno-associated virus subtype 9 (AAV9) in the mutant hearts partially rescued the cryoinjury-induced cardiac hypertrophy, promoted cardiomyocyte replication and improved heart function after injury. Altogether, our data demonstrate that GATA4 is required for neonatal heart regeneration through regulation of Fgf16, suggesting that paracrine factors could be of potential use in promoting myocardial repair.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Huang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Tian
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lingjuan
authors.initials: L
authors.lastname: He
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nie
authors.affiliation: State 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.
authors.forename: Shengshou
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Departments of Genetics, Pediatrics and Medicine (Cardiology), Albert Einstein College of Medicine of Yeshiva University, 1301 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pu
authors.affiliation: Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, 999077 China.
authors.forename: Kathy O
authors.initials: KO
authors.lastname: Lui
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210 China zhoubin@sibs.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D049109:Cell Proliferation; D000229:Dependovirus / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D017353:Gene Deletion; D006321:Heart / Q000503:physiopathology*; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D009928:Organ Specificity; D010641:Phenotype; D012038:Regeneration
chemical_list: C484686:Fgf16 protein, mouse; D050991:GATA4 Transcription Factor; D005346:Fibroblast Growth Factors
keywords: Cardiomyocyte proliferation; FGF16; GATA4; Heart regeneration; Heart repair