The dual‐specificity phosphatase 8 (Dusp8) regulates cardiac hypertrophic response in vitro and in vivo

Abstract

BackgroundPhosphorylation and dephosphorylation of mitogen‐activated protein kinases (MAPKs) play important roles in regulating cardiac hypertrophy, remodeling, and heart failure. Dual‐specificity phosphatases (Dusps) directly dephosphorylate and inactivate each of the MAPK terminal kinases (ERK, p38, JNK) within 30 to 60 minutes activation. In this study, we generated mice and mouse embryonic fibroblasts (MEFs) lacking DUSP8 gene and determined the role of Dusp8 in regulating c‐Jun N‐terminal kinases (JNK1/2) signaling in neonatal myocyte culture and mouse heart. We hypothesized that knockout of Dusp8 will lead to increased JNK phosphorylation and decreased cardiac hypertrophy.MethodsDUSP8 null mice were generated using traditional gene‐targeting approach to delete exon 5 and 6. Phenylephrine was injected at final concentration of 10 mg/kg using 2‐month‐old mice.Results: Adenovirus mediated Dusp8 overexpression in cultured cardiomyocytes resulted in decreased JNK1/2 phosphorylation but not that of p38 and ERK1/2, indicating Dusp8 is specific for JNK dephosphorylation. In contrast, injection of Dusp8 null mice with phenylephrine led to sustained JNK phosphorylation compared to that of WT mice, which was also true for the JNK signaling in Dusp8 null MEF cells. Dusp8 null mice had reduced left ventricular weight/body weight ratio at both baseline and angiotensin II/phenylephrine stimulation condition. At cellular level, we found that overexpression of Dusp8 led to increased nuclear accumulation of NFAT and expression of hypertrophy gene ANF.ConclusionsThe results of the present study indicate that knockout of Dusp8 is cardioprotective through increasing JNK phosphorylation to prevent NAFT signaling induced cardiomyopathy.