Abstract P1164: Elevated Erk1/2 Signaling Contributes To The Development Of Diabetic Cardiomyopathy

Abstract

Background: About 19%-26% of the obese patients develop diabetic cardiomyopathy (DCM) characterized by ventricular hypertrophy, fibrosis, and contractile dysfunction. Although many studies have investigated the potential causes of DCM, the pathophysiology of this disease has yet been to be fully characterized. Objective: To determine whether extracellular signal-regulated kinase 1/2 (ERK1/2) are involved in the development of DCM. Materials and Methods: Both streptozotocin (STZ)-induced type I and db/db type II diabetic mice were utilized to compare the ERK1/2 phosphorylation level in mouse hearts. To determine the gain-of-function of ERK1/2 signaling in DCM, both control and dual specific phosphatase 6 and 8 knockout mice (DKO) mice were administered streptozotocin (STZ) to induce elevated serum glucose. After 12 weeks of treatment, mouse body weight, heart weight/histology, and disease markers were compared. As a loss-of-function study, U0126 was utilized to inhibit ERK1/2 activity in both streptozotocin (STZ)-induced type I and db/db type II diabetic mice to determine whether DCM markers are influenced. Results: In both type I and II diabetic mouse hearts, ERK1/2 phosphorylation level was significantly elevated. STZ treatment for 2 weeks induced similar increases in serum glucose in both WT and DKO mice. After 12 weeks of STZ treatment, DKO mice developed greater cardiac atrophy and increased levels of ANF, BNP, beta myosin heavy chain gene expression. In comparison, U0126-mediated pharmacological inhibition of ERK1/2 for 12 weeks significantly improved the cardiac function in both type I and II diabetic mouse models. Conclusion: Elevated ERK1/2 signaling contributes to the process of DCM, suggesting ERK1/2 could be therapeutic targets for the treatment of this disease.