Leucine‐Rich Repeat‐Containing G Protein‐Coupled Receptor 6 Ameliorates Pressure Overload‐Induced Cardiac Hypertrophy by Regulating Cardiomyocyte Metabolic Reprogramming

Abstract Metabolic reprogramming is a pivotal mechanism in the pathogenesis of pathological cardiac hypertrophy. Leucine‐rich repeat‐containing G protein‐coupled receptor 6 (Lgr6) has emerged as a significant player in cardiovascular diseases. In this study, the potential of Lgr6 to counteract pressure overload (PO)‐induced cardiac hypertrophy is investigated, and the underlying mechanisms involved are elucidated. Transverse aortic constriction (TAC) is induced to establish an in vivo cardiac hypertrophy model. Adeno‐associated virus 9 and adenovirus vectors are utilized to knock down and overexpress Lgr6 in cardiomyocytes, respectively. The effects of Lgr6 and its downstream molecules are subsequently determined using RNA sequencing and chromatin immunoprecipitation. Significant downregulation of Lgr6 expression is observed in the heart after TAC and in cardiomyocytes treated with phenylephrine. Lgr6 deficiency accelerated and Lgr6 overexpression inhibits cardiac hypertrophy and dysfunction after TAC. Mechanistically, the in vivo and in vitro experiments suggest that Lgr6 regulates the expression of ubiquitin specific protease 4 (USP4) and peroxisome proliferator‐activated receptor alpha (PPARα) by activating the cGMP/PKG/CREB1 signalling pathway, thereby regulating cardiomyocyte metabolic reprogramming after PO. Targeting Lgr6 can be a potential therapeutic strategy to treat pathological cardiac hypertrophy.