DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling

Abstract

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 cardiac myocyte 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 cardiac myocytes from Dusp8 gene-deleted mice were thicker and shorter, while DUSP8 overexpression promoted cardiac myocyte 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 cardiac myocytes that then alters the length-width growth dynamics of individual cardiac myocytes, which further alters contractility, ventricular remodeling and disease susceptibility.

Regulation of cardiac hypertrophy and remodeling through the dual-specificity MAPK phosphatases (DUSPs)

“…As discussed earlier, DUSP6 Tg mice showed alterations in cardiac ventricular remodeling with pressure overload, such as greater dilation and loss of ventricular performance [45]. This is consistent with the phenotype of Mapk1 /3 (ERK1/2) heart-specific null mice that also showed failure with ventricular dilation and increase in myocyte growth in the long axis [28, 44]. Taken together, manipulation of ERK1/2 signaling by DUSP6 suggests that ERK1/2 are not required for mediating hypertrophy per se, but rather that DUSP6-ERK1/2 influence the balance between concentric and eccentric growth of the heart with myocytes growing in either their long or short axis.…”

“…The second and cytoplasmic-localized group includes DUSP6/MKP-3, DUSP7 and DUSP9/MKP4, which are largely specific for ERK1/2 dephosphorylation [25]. The final group includes the cytoplasmic and nuclear localized DUSPs, including DUSP8 (M3/6), DUSP10/MKP5, DUSP14/MKP6, and DUSP16/MKP7, which are thought to have greater specificity for JNK and p38, although DUSP14 is also involved in inactivation of transforming growth factor beta-activated kinase 1 (TAK1) and DUSP8 appears to be more specific for ERK1/2 [27, 28]. The exact specificity of a given DUSP protein for selected MAPKs is often difficult to determine as it can vary between cell-types and depend on the type of assay empolyed.…”

“…The exact specificity of a given DUSP protein for selected MAPKs is often difficult to determine as it can vary between cell-types and depend on the type of assay empolyed. For example, DUSP8 was originally shown to be JNK-specific based on work in cultured cells [29] but in knock-out (KO) mice lacking Dusp8 we have shown a greater preference for ERK1/2 inactivation within the heart [28]. …”

“…As briefly mentioned above, the DUSPs are transiently induced in response to growth factors or cellular stresses, although some are more constitutively expressed and have basal effects on MAPK activity [28, 36]. The induction and transcription of DUSPs are dependent on the activation of MAPKs, which creates a “self-limiting” feed-back loop.…”

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

“…Eccentric growth at the cellular level is conceptually coupled with DCM and progression into HF at the organ level (46) and was shown to depend on MAPK activity (16,17,47). It has not been clearly established, however, whether elongation and thinning of cardiomyocytes initiate or culminate from disease.…”