Abstract 155: ATF6 is a Mediator of Cardiac Hypertrophy During Pressure Overload in the Mouse Heart

Abstract

The endoplasmic reticulum (ER) stress response is one of many signaling events activated in the heart in response to injury and/or cardiac hypertrophy, although the role that this response pathway plays in such events remains under investigation. Recently, our laboratory demonstrated that overexpression of thrombospondin-4 (Thbs4) resulted in a protective ER stress response via activation of activating transcription factor 6 (ATF6), and that mice gene-deleted for Thbs4 demonstrated compromised ER stress signaling and decreased survival after transverse aortic constriction (TAC) or myocardial infarction (MI) surgery. Here we confirm that Thbs4-mediated expansion of the ER compartment requires ATF6 and examine whether the protective ER stress response mediated by transgenic overexpression of Thbs4 is eliminated when crossed with gene-deleted mice lacking ATF6. We also examined cardiac-specific transgenic mice overexpressing the transcriptionally-active ATF6 N-terminus, as well as mice gene-deleted for ATF6, in combination with disease stimuli including TAC and MI surgery. We find that ATF6 proteins are required for compensatory hypertrophy in the mouse heart and that loss of these proteins results in accelerated decompensation and failure, likely due to reductions in ER folding capacity that is required for the increased protein production necessary for cardiac hypertrophy. These results firmly position ATF6 as an essential regulator of compensatory cardiac hypertrophy during disease.