PRMT5 Prevents Dilated Cardiomyopathy via Suppression of Protein O-GlcNAcylation

Rationale: Protein O-GlcNAcylation is dynamically regulated by 2 key enzymes, OGT (O-GlcNAc transferase) and OGA (O-GlcNAcase). Excessive protein O-GlcNAcylation contributes to dilated cardiomyopathy (DCM), but its regulatory mechanisms are not fully understood. The PRMT5 (protein arginine methyltransferase 5) is the major type II arginine methyltransferase, which plays critical physiological roles by symmetrically dimethylating various downstream targets including proteins involved in RNA splicing. However, its function in regulating protein O-GlcNAcylation and DCM is unexplored. Objective: To elucidate the physiological function of PRMT5 and the mechanism underlying its role in regulating cardiac O-GlcNAcylation and homeostasis. Methods and Results: Conditional gene knockout was used to study the in vivo function of PRMT5 in regulating cardiac homeostasis. An integrated analysis of transcriptomic and metabolomic profiles was performed to investigate the molecular mechanism. Adeno-associated virus 9-mediated gene delivery in the mouse was used to study the protein O-GlcNAcylation in Prmt5 deficiency-induced DCM. PRMT5 mRNA was decreased in human DCM hearts, and cardiomyocyte-specific Prmt5 deletion in mice resulted in DCM and heart failure. Transcriptomic and metabolomic profiling identified increased O-GlcNAcylation in the hearts of Prmt5-knockout mice. Mechanistically, Prmt5 deletion suppressed OGA expression by inhibiting the transcription of Oga and triggering its aberrant splicing. Consistently, a positive correlation of PRMT5 and OGA was identified in human DCM hearts. Notably, gene therapy with adeno-associated virus 9 encoding the correctly spliced Oga normalized the cardiac protein O-GlcNAcylation levels and partially rescued the dilation and dysfunction of the hearts in Prmt5-knockout mice. Conclusions: Our data demonstrate a novel function of PRMT5 in regulating protein O-GlcNAcylation to maintain cardiac homeostasis, suggesting that targeting the PRMT5-OGA axis could be a potential strategy for treating DCM.