DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling
Rationale: Mitogen-activated protein kinase (MAPK) signaling regulates the growth response of the adult myocardium in response to increased cardiac workload or pathologic insults. The dual-specificity phosphatases (DUSPs) are critical effectors that dephosphorylate the MAPKs to control the basal tone, amplitude and duration of MAPK signaling.
Objective:: To examine the dual-specificity phosphatase 8 (DUSP8) as a regulator of MAPK signaling in the heart and its impact on ventricular and cardiomyocyte growth dynamics.
Methods and Results: Dusp8 gene-deleted mice as well as 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 two surgery-induced disease models. Cardiac-specific overexpression of DUSP8 produced spontaneous eccentric remodeling and ventricular dilation with heart failure. At the cellular level, adult cardiomyocytes from Dusp8 gene-deleted mice were thicker and shorter, while DUSP8 overexpression promoted cardiomyocyte lengthening with a loss of thickness. Mechanistically, activation of extracellular signal-regulated kinases 1/2 (ERK1/2) were selectively increased in Dusp8 gene-deleted hearts at baseline as well as following acute pathologic stress stimulation, while p38 MAPK and c-Jun N-terminal kinases were unaffected.
Conclusions: These results indicate that DUSP8 controls basal and acute stress-induced ERK1/2 signaling in adult cardiomyocytes that then alters the length-width growth dynamics of individual cardiomyocytes, which further alters contractility, ventricular remodeling and disease susceptibility.
- Dual-specificity phosphatase
- concentric remodeling
- mitogen-activated protein kinase
- cardiac hypertrophy
- heart failure
- signaling pathways
- dilated cardiomyopathy
- Received December 22, 2015.
- Revision received May 10, 2016.
- Accepted May 25, 2016.