Abstract Body: Background: Mechanisms of metabolic regulation are central to cardiac homeostasis and responses to stress that drive heart failure. Neurofibromin 2 (NF2) is a tumor suppressor that influences a wide range of cellular functions yet remains understudied in the heart. We previously demonstrated that NF2 mediates cardiomyocyte apoptosis and cardiac injury caused by acute myocardial infarction.
Research Aim: The role of NF2 in heart failure has not been investigated and is the focus of this study.
Approach: We generated cardiomyocyte-specific NF2 knockout (cKO) mice and used transverse aortic constriction (TAC) to generate chronic pressure overload (PO) stress, which elicits cardiac remodeling and failure. Complementary cell-based experiments were performed in neonatal rat ventricular myocytes (NRVMs). We analyzed cardiac function by echocardiographic and hemodynamic analysis. We used RNAseq and validated the novel findings using promoter pulldown, proteomics, Seahorse metabolic profiling, AAV-based approaches, and biochemical analyses to investigate underlying mechanisms.
Results: NF2 was dynamically upregulated in the early phase of PO, and suppressed during chronic PO, in wild-type mouse myocardium. Following TAC, NF2 cKO hearts unexpectedly showed significantly worsened cardiac function and exacerbated adverse remodeling, compared to controls. RNAseq analysis followed by qPCR indicated downregulation of multiple metabolic pathways and impaired Estrogen Related Receptor (ERR) activity in NF2 cKO hearts. Cardiac ERRa/g expression and fatty acid oxidation were decreased, while lipid accumulation increased, in NF2 cKO mice. Studies in NRVMs demonstrated that NF2 promotes ERR isoform transcription, and NF2 depletion impaired mitochondrial respiration, which was reversed by normalizing ERRg expression. Restoration of ERRg in vivo significantly improved the cardiac remodeling and dysfunction observed in NF2 cKO mice after PO. Additionally, NF2, ERRa/g and FAO genes were downregulated in human heart failure biopsies.
Conclusion: Our study provides evidence that NF2 signaling represents a novel mechanism to facilitate ERR isoform expression and promote energetic resiliency during chronic cardiac stress.