MRNA IN HEART · mRNA translational regulation in heart failure

Protein synthesis is among the principal biological processes underlying cardiac hypertrophy, an early event in many forms of heart failure (HF). It is associated with worsening of cardiac function after long-term exposure to noxae. The rate-limiting step of protein synthesis is mRNA translation, which is controlled by factors involved in initiation and/or elongation. 4E-BPs regulate the translation of a subset of mRNAs by competing with eIF4G for binding to eIF4E, preventing the assembly of eIF4F and hence inhibiting translation. The overall aim of this project is to determine the role of the Eif4E-binding proteins in protein synthesis in the cardiomyocyte, identifying 4E-BP-regulated mRNAs that mediate cardiac function in normal and disease states.We recently generated a cardiac-specific mTOR-/- mouse line and found that it develops rapid cardiac dilation and impaired heart function without undergoing an initial hypertrophic phase; mortality reached 100% within 8 weeks of inducing the deletion with tamoxifen (TMX). A striking feature of this HF model is the accumulation of the dephosphorylated (active) form of the mTOR substrate 4E-BP1 within the myocardium. We noticed that this occurs also in other models of HF, including embryonic mTOR-/- heart, pressure-overloaded wild-type (WT) mice, raptor-/- mice, and MLP-/- mice. When mTOR-/- mice were crossed with 4E-BP1-/- mice, 4E-BP1 accumulation was abolished, cardiac function was ameliorated, and survival was significantly, albeit only partially, improved. Therefore, we hypothesized that elevated dephosphorylated 4E-BP is linked to heart failure through translational inhibition of a subset of mTOR-activated mRNAs. This project will add new, significant information on the regulation of gene expression in compensatory hypertrophy after stress and on the pathophysiology of myocardial hypertrophy and failure.