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Circ Res. 2016 Jul 8;119(2):249-60. doi: 10.1161/CIRCRESAHA.115.308238. Epub 2016 May 25.

DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling.

Author information

1
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.).
2
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.

Abstract

RATIONALE:

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.

OBJECTIVE:

To examine DUSP8 as a regulator of MAPK signaling in the heart and its impact on ventricular and cardiac myocyte growth dynamics.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

dilated cardiomyopathy; disease susceptibility; dual-specificity phosphatase; heart failure; myocardium

PMID:
27225478
PMCID:
PMC4938738
DOI:
10.1161/CIRCRESAHA.115.308238
[Indexed for MEDLINE]
Free PMC Article

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