title: Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling.
abstract: BACKGROUND
  Hypertensive ventricular remodeling is a common cause of heart failure. However, the molecular mechanisms regulating ventricular remodeling remain poorly understood.
  
  
  METHODS
  We used a discovery-driven/nonbiased approach to identify increased activating transcription factor 3 (ATF3) expression in hypertensive heart. We used loss/gain of function approaches to understand the role of ATF3 in heart failure. We also examined the mechanisms through transcriptome, chromatin immunoprecipitation sequencing analysis, and in vivo and in vitro experiments.
  
  
  RESULTS
  ATF3 expression increased in murine hypertensive heart and human hypertrophic heart. Cardiac fibroblast cells are the primary cell type expressing high ATF3 levels in response to hypertensive stimuli. ATF3 knockout (ATF3KO) markedly exaggerated hypertensive ventricular remodeling, a state rescued by lentivirus-mediated/miRNA-aided cardiac fibroblast-selective ATF3 overexpression. Conversely, conditional cardiac fibroblast cell-specific ATF3 transgenic overexpression significantly ameliorated ventricular remodeling and heart failure. We identified Map2K3 as a novel ATF3 target. ATF3 binds with the Map2K3 promoter, recruiting HDAC1, resulting in Map2K3 gene-associated histone deacetylation, thereby inhibiting Map2K3 expression. Genetic Map2K3 knockdown rescued the profibrotic/hypertrophic phenotype in ATF3KO cells. Last, we demonstrated that p38 is the downstream molecule of Map2K3 mediating the profibrotic/hypertrophic effects in ATF3KO animals. Inhibition of p38 signaling reduced transforming growth factor-β signaling-related profibrotic and hypertrophic gene expression, and blocked exaggerated cardiac remodeling in ATF3KO cells.
  
  
  CONCLUSIONS
  Our study provides the first evidence that ATF3 upregulation in cardiac fibroblasts in response to hypertensive stimuli protects the heart by suppressing Map2K3 expression and subsequent p38-transforming growth factor-β signaling. These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive cardiac remodeling.
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.).
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.).
authors.forename: Zhenya
authors.initials: Z
authors.lastname: Li
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.).
authors.forename: Congcong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.).
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.).
authors.forename: Yina
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.).
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Wang
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.).
authors.forename: Wayne
authors.initials: W
authors.lastname: Bond Lau
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.). jdu@bcm.edu xin.ma@jefferson.edu.
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
authors.affiliation: From Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y.L., Z.L., C.Z., P.L., Y.W., C.W., J.D.); and Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.). jdu@bcm.edu xin.ma@jefferson.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000107:Acetylation; D051700:Activating Transcription Factor 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D006657:Histones; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; C482531:Map2k3 protein, mouse; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1
keywords: activating transcription factor 3; fibroblast; heart failure; p38 mitogen-activated protein kinases