title: Hydrogen peroxide primes heart regeneration with a derepression mechanism.
abstract: While the adult human heart has very limited regenerative potential, the adult zebrafish heart can fully regenerate after 20% ventricular resection. Although previous reports suggest that developmental signaling pathways such as FGF and PDGF are reused in adult heart regeneration, the underlying intracellular mechanisms remain largely unknown. Here we show that H2O2 acts as a novel epicardial and myocardial signal to prime the heart for regeneration in adult zebrafish. Live imaging of intact hearts revealed highly localized H2O2 (~30 μM) production in the epicardium and adjacent compact myocardium at the resection site. Decreasing H2O2 formation with the Duox inhibitors diphenyleneiodonium (DPI) or apocynin, or scavenging H2O2 by catalase overexpression markedly impaired cardiac regeneration while exogenous H2O2 rescued the inhibitory effects of DPI on cardiac regeneration, indicating that H2O2 is an essential and sufficient signal in this process. Mechanistically, elevated H2O2 destabilized the redox-sensitive phosphatase Dusp6 and hence increased the phosphorylation of Erk1/2. The Dusp6 inhibitor BCI achieved similar pro-regenerative effects while transgenic overexpression of dusp6 impaired cardiac regeneration. H2O2 plays a dual role in recruiting immune cells and promoting heart regeneration through two relatively independent pathways. We conclude that H2O2 potentially generated from Duox/Nox2 promotes heart regeneration in zebrafish by unleashing MAP kinase signaling through a derepression mechanism involving Dusp6.
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Peidong
authors.initials: P
authors.lastname: Han
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Xiao-Hai
authors.initials: XH
authors.lastname: Zhou
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Chang
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Cheng-Lu
authors.initials: CL
authors.lastname: Xiao
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Shouyu
authors.initials: S
authors.lastname: Yan
authors.affiliation: 1] State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China [2] College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: He
authors.initials: H
authors.lastname: Ren
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Xin-Zhuang
authors.initials: XZ
authors.lastname: Yang
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.affiliation: 1] Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China [2] State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China.
authors.forename: Boyang
authors.initials: B
authors.lastname: Tang
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Ju-Peng
authors.initials: JP
authors.lastname: Diao
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: 1] State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China [2] College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Chuanmao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Chuan-Yun
authors.initials: CY
authors.lastname: Li
authors.affiliation: 1] Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China [2] State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China [3] Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Xiong
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D012097:Repressor Proteins; D029961:Zebrafish Proteins; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex