Abstract 352: Dual Specificity Phosphatase 8 (dusp8) Regulates Cardiac Remodeling and Function by Affecting Erk1/2 Phosphorylation

Abstract

Rationale: Mitogen-activated protein kinases (MAPKs) are activated in the heart by various stress-inducing stimuli, where they participate in cardiac hypertrophy, contractility, and cell death. A family of dual-specificity phosphatases (DUSPs) directly inactivates each of the MAPK terminal effectors, thus providing a feedback mechanism to regulate the activity and recycling of MAPKs. How DUSPs regulate MAPK signaling to influence cardiac function is not well understood.

Objective: To determine the role of DUSP8 in regulating MAPK signaling and the effect on cardiac disease.

Methods and Results: We generated DUSP8 null (KO) and inducible cardiac specific DUSP8 transgenic mice to assess the effect on cardiac structure-function at baseline and with stress-responsiveness. Loss of DUSP8 did not alter cardiac structure-function or MAPK phosphorylation at baseline. However, with pressure overload or myocardial infarction injury, DUSP8 KO mice developed concentric hypertrophy with preserved cardiac function compared to wild type controls, suggesting a cardioprotective role for loss of DUSP8. DUSP8 transgenic mice developed cardiac hypertrophy at baseline as evidenced by elevated expression of hypertrophic marker genes as well as increased heart weights and cross sectional area of the myocytes. DUSP8 transgenic mice also had mild interstitial fibrosis and reduced fractional shortening. Biochemical analysis of MAPK phosphorylation demonstrated increased ERK phosphorylation in KO mice upon stress, suggesting a molecular mechanism underlying the increased concentric growth of DUSP8 KO cardiomyocytes.

Conclusions: Taken together, these data demonstrate that DUSP8 modulates ERK phosphorylation to influence cardiomyocyte growth and consequent cardiac function with injury. Further analysis of MAPK phosphorylation in DUSP8 transgenic mice will provide more insight into DUSP8-ERK signaling in the heart.