Physiological and Pathological Hypertrophy: Target Therapeutics and the Role of Inhibiting ERK1/2 THR188 Autophosphorylation

Abstract

Two broad categories of cardiac hypertrophy exist: pathological and physiological. The physiological response, induced by postnatal growth and exercise training, involves cellular signaling that results in the activation of the serine-threonine kinase isoform 一 Akt. Akt is responsible for cell survival, cell growth and proliferation, and cellular metabolism. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are members of the mitogen-activated protein kinase family that mediate pathological hypertrophy. During the pathological response, pressure overload on the heart wall and vasoactive factors ultimately result in the activation of ERK1/2. A separated pathway, using β1-adrenergic receptors, results in the autophosphorylation of ERK2 at residue Thr188, which translocates to the nucleus and activates hypertrophic factors. The central hypothesis is that inhibiting ERK1/2 Thr188 autophosphorylation will inhibit pathological hypertrophy. For example, N-terminal truncated phosducin could potentially inhibit pathological hypertrophy by inhibiting ERK1/2 Thr188 autophosphorylation. This thesis focuses on determining the differences in signaling pathways that mediate physiological and pathological cardiac hypertrophy, current therapeutic targets, and the potential therapeutic role of inhibiting ERK1/2 Thr188 autophosphorylation.