title: DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling.
abstract: Mitogen-activated protein kinase (MAPK) signaling regulates the growth response of the adult myocardium in response to increased cardiac workload or pathological insults. The dual-specificity phosphatases (DUSPs) are critical effectors, which dephosphorylate the MAPKs to control the basal tone, amplitude, and duration of MAPK signaling.
  
  
  
  To examine DUSP8 as a regulator of MAPK signaling in the heart and its impact on ventricular and cardiac myocyte growth dynamics.
  
  
  
  Dusp8 gene-deleted mice and transgenic mice with inducible expression of DUSP8 in the heart were used here to investigate how this MAPK-phosphatase might regulate intracellular signaling and cardiac growth dynamics in vivo. Dusp8 gene-deleted mice were mildly hypercontractile at baseline with a cardiac phenotype of concentric ventricular remodeling, which protected them from progressing towards heart failure in 2 surgery-induced disease models. Cardiac-specific overexpression of DUSP8 produced spontaneous eccentric remodeling and ventricular dilation with heart failure. At the cellular level, adult cardiac myocytes from Dusp8 gene-deleted mice were thicker and shorter, whereas DUSP8 overexpression promoted cardiac myocyte lengthening with a loss of thickness. Mechanistically, activation of extracellular signal-regulated kinases 1/2 were selectively increased in Dusp8 gene-deleted hearts at baseline and following acute pathological stress stimulation, whereas p38 MAPK and c-Jun N-terminal kinases were mostly unaffected.
  
  
  
  These results indicate that DUSP8 controls basal and acute stress-induced extracellular signal-regulated kinases 1/2 signaling in adult cardiac myocytes that then alters the length-width growth dynamics of individual cardiac myocytes, which further alters contractility, ventricular remodeling, and disease susceptibility.
authors.affiliation: From the Department of Pediatrics, University of Cincinnati (R.L., J.H.v.B., A.J.Y., R.J.V., M.M., J.D.M.) and Howard Hughes Medical Institute (J.D.M.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Division of Cardiology, Department of Medicine, Lillehei Heart Institute, University of Minnesota, St. Paul (J.H.v.B.).
authors.forename: Ruijie
authors.initials: R
authors.lastname: Liu
authors.affiliation: From the Department of Pediatrics, University of Cincinnati (R.L., J.H.v.B., A.J.Y., R.J.V., M.M., J.D.M.) and Howard Hughes Medical Institute (J.D.M.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Division of Cardiology, Department of Medicine, Lillehei Heart Institute, University of Minnesota, St. Paul (J.H.v.B.).
authors.forename: Jop H
authors.initials: JH
authors.lastname: van Berlo
authors.affiliation: From the Department of Pediatrics, University of Cincinnati (R.L., J.H.v.B., A.J.Y., R.J.V., M.M., J.D.M.) and Howard Hughes Medical Institute (J.D.M.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Division of Cardiology, Department of Medicine, Lillehei Heart Institute, University of Minnesota, St. Paul (J.H.v.B.).
authors.forename: Allen J
authors.initials: AJ
authors.lastname: York
authors.affiliation: From the Department of Pediatrics, University of Cincinnati (R.L., J.H.v.B., A.J.Y., R.J.V., M.M., J.D.M.) and Howard Hughes Medical Institute (J.D.M.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Division of Cardiology, Department of Medicine, Lillehei Heart Institute, University of Minnesota, St. Paul (J.H.v.B.).
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Vagnozzi
authors.affiliation: From the Department of Pediatrics, University of Cincinnati (R.L., J.H.v.B., A.J.Y., R.J.V., M.M., J.D.M.) and Howard Hughes Medical Institute (J.D.M.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Division of Cardiology, Department of Medicine, Lillehei Heart Institute, University of Minnesota, St. Paul (J.H.v.B.).
authors.forename: Marjorie
authors.initials: M
authors.lastname: Maillet
authors.affiliation: From the Department of Pediatrics, University of Cincinnati (R.L., J.H.v.B., A.J.Y., R.J.V., M.M., J.D.M.) and Howard Hughes Medical Institute (J.D.M.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Division of Cardiology, Department of Medicine, Lillehei Heart Institute, University of Minnesota, St. Paul (J.H.v.B.). jeff.molkentin@cchmc.org.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D054637:Dual-Specificity Phosphatases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C578383:DUSP8 protein, mouse; D054637:Dual-Specificity Phosphatases
keywords: dilated cardiomyopathy; disease susceptibility; dual-specificity phosphatase; heart failure; myocardium