317 - PTP1B Regulates Argonaute 2 Activity, MED 13 Expression and Cardiac Hypertrophy

Abstract

Cardiac hypertrophy involves the expression of a gene program that occurs when cardiomyocytes are continuously exposed to stresses. The initial determinant is biomechanical stretch, with the concomitant increased expression and release of growth factors, Ras activation and reactive oxygen species (ROS) signaling. Given the importance of ROS in the transition from cardiac hypertrophy to heart failure and the documented inhibition of Protein Tyrosine Phosphatases (PTPs) by ROS, we hypothesized and explored whether specific PTPs could act as checkpoints in this process. We have identified PTP1B as a target of ROS in hearts undergoing hypertrophy. To understand the role of PTP1B in cardiac hypertrophy, we generated cardiomyocyte-specific PTP1B knockout (PTP1B cKO) mice. Subjecting PTP1B cKO mice to pressure overload (PO) caused a dramatic left ventricular dilation and several features of heart failure when compared to control mice subjected to PO for the same period. Characterization of mRNAs expressed in hypertrophy revealed that the increased expression of b-MHC observed in control mice subjected to PO was compromised in PTP1B cKO-PO mice. We identified a member of the RNA-Induced Silencing Complex, Argonaute 2 (AGO2), as a substrate of PTP1B in PO hearts and observed increased AGO2 phosphotyrosine-393 levels. A miRNA microarray of PO hearts revealed an uncoupling between miR abundance and gene silencing in PTP1B cKO hearts: in hypertrophic PTP1B cKO hearts, the regulation of Mediator 13 (MED13) by AGO2-miR208 was compromised, leading to the activation of Thyroid Receptor b1 (TRb1) and to the suppression of b-MHC expression. Preventing TRb1 activation by inhibiting thyroid hormone synthesis resulted in up-regulation of b-MHC, and recovered the phenotype. We propose a model in which ROS inhibition of PTP1B regulates AGO2 activity, MED13 expression and contributes to cardiac hypertrophy and heart failure.