Abstract 441: Neurofibromin 2 Regulates Metabolism in the Heart

Background: Neurofibromin 2 (NF2) is a tumor suppressor and signaling platform that can engage the Hippo pathway to modulate cell proliferation and survival. We previously demonstrated that NF2 mediates injury caused by acute myocardial infarction (MI) through inhibition of the Hippo target YAP. However, NF2 function in the heart remains largely uncharacterized. This study sought to determine whether NF2 contributes to cardiac remodeling, dysfunction, and heart failure resulting from chronic stress. Methods and Results: We used a transverse aortic constriction (TAC) model to generate pressure overload (PO), which elicits cardiac hypertrophy, remodeling and heart failure. We found that NF2 is transiently upregulated in WT C57Bl/6J myocardium in response to PO. To investigate if increased NF2 contributes to pathology, we used cardiomyocyte-specific (αMHC-Cre) NF2 knockout (CKO) mice. At baseline, adult NF2 CKO mice had normal cardiac morphology and function. However, following TAC, NF2 CKO hearts unexpectedly showed worsened cardiac function compared to littermate controls. No differences in the extent of TAC-induced hypertrophy or apoptosis were observed between genotypes. RNAseq analysis indicated downregulation of several metabolic pathways including oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) in unstressed NF2 CKO hearts. RNAseq identified, and qPCR confirmed, downregulation of ERRβ and ERRγ expression and function in NF2 CKO hearts, as well as ATP content. Critical ETC genes were also suppressed in NF2 CKO hearts after 3 days PO. Experiments in neonatal rat cardiomyocytes (NRCM) confirmed that altered ERRβ and ERRγ expression and function, as well as ATP content, by NF2 is cell autonomous. Mechanistically, we discovered that nuclear NF2 is enriched following TAC, and that NF2 associates with the proximal promoter regions of ERRβ and ERRγ using DNA pulldown assay. We also found that NF2 activates transcription in NRCMs using the Gal4-UAS system. Future studies will identify transcription factors important for mediating this response. Conclusion: Myocardial NF2 is transiently upregulated and may be compensatory during PO through preservation of metabolic gene expression and energy content in the heart.