Abstract P245: Loss of Steroid Receptor Coactivator-2 in the Heart Results in a Return to the Fetal Gene Program

Abstract

Steroid Receptor Coactivator-2 (SRC-2) is an integral transcriptional mediator of metabolism throughout the body with roles in both fatty acid and carbohydrate metabolism. Based on the critical link between cardiac function and cardiac metabolism, which itself has dynamic interplay between both fatty acid and carbohydrate use, we sought to determine if SRC-2 plays a role in controlling cardiac metabolism. Hearts from SRC-2-/- mice were analyzed by extensive gene expression profiling of major metabolic enzymes in fuel usage pathways as well as metabolomic analysis of major metabolites. Our results indicate that under normal conditions, loss of SRC-2 compromises the ability of the adult heart to metabolize fatty acid as its sole fuel source. We observe a gene expression profile that mimics the fetal heart and a metabolomic profile that suggests a reliance on anaerobic conversion of glucose to lactate for energy. This fetal gene switch is paralleled with changes of sarcomeric gene expression, along with several genes altered in response to stress. Interestingly, this long-term adaptive response is adequate to maintain cardiac function under normal conditions. However, SRC-2-/- mice do show impaired cardiac function as compared to SRC-2+/+ mice under hemodynamic stress from aortic banding. Surprisingly, this is accompanied by the absence of hypertrophy, which may be explained by decreased expression of serum response factor (SRF) and several of the transcription factors with which SRF is known to act. Taken together, loss of SRC-2 results in a cardiac phenotype characterized by a return to the fetal gene program that mimics the state of a stressed and/or aging heart. Further investigation of this mouse model may play an important role in understanding the mechanisms underlying the transcriptional events surrounding cardiac metabolic remodeling.