Extracellular Regulated Kinases Protects Against Maladaptive Cardiac Hypertrophy Following Chronic Pressure Overload - The 65th Annual Conference of the Israel Heart Society & The Israel Society of Cardiothoracic Surgery, 24-25 April 2018

Michael Mutlak Department of Physiology, The Rappaport Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel Izhak Kehat Department of Physiology, The Rappaport Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel Department of Cardiology and the Clinical Research Institute at Rambam, Rambam Medical Center, Haifa, Israel

Background: Cardiac hypertrophy is a major risk factor for the development of heart failure, arrhythmias and sudden cardiac death. One of the great challenges in the field of cardiac hypertrophy is to differentiate between the adaptive processes that help to normalizing wall stress and maintain function, form the maladaptive ones. Both animal and patient data have consistently shown that the Extracellular regulated kinases (ERK1/2) pathway is activated in cardiac hypertrophy, with phosphorylation of both the TEY canonical site and on Thr207/Thr188 on ERK1/2. However there are conflicting studies about the causal role of activated ERK1/2 in cardiac hypertrophy, especially when phosphorylated on Thr207/Thr188.

Objective: To determine the role of activated ERK1 in cardiac hypertrophy and its effect on cardiac function following pressure overload.

Methods and Results: We generated transgenic mice expressing a gain of function mutant (ERK1^R84S) in the heart that is constitutively phosphorylated on both the TEY and on Thr207. These mice demonstrated mild baseline cardiac hypertrophy with increased heart weight, increased myocyte surface area, and elevated hypertrophic marker genes, but without fibrosis. In response to pressure overload, these mice were protected, and although they developed comparable increase in heart size as controls, echocardiography and MRI demonstrated preservation of cardiac function. Histopathological studies and marker gene assessment similarly showed decreased fibrosis.

Conclusion: ERK activation induces mild adaptive cardiac hypertrophy in-vivo, and is protective in pressure overload, preserving cardiac function and reducing fibrosis. Activation of ERK may be a therapeutic strategy to preserve cardiac function in the presence of increased load.