PRMT2 Aggravates Pressure Overload-induced Cardiac Remodeling by Promoting Endothelial Phenotypic Transition via Snail1 Methylation.

Abstract

Purpose: Endothelial-to-mesenchymal transition (EndMT) is implicated in cardiac remodeling under pathological stress, although its full in vivo occurrence may be context-dependent. Emerging evidence suggests that protein methylation is an important post-translational modification involved in regulating endothelial phenotypic transition (EndMT-like process). However, the role of protein arginine methyltransferase 2 (PRMT2), a key protein arginine methyltransferase, in modulating endothelial phenotypic transition-particularly in the context of cardiac remodeling-remains poorly understood.

Methods: A transverse aortic constriction (TAC) mouse model was used to induce cardiac remodeling, and adeno-associated virus serotype 9 (AAV9) was administered to specifically silence PRMT2 in endothelial cells.

Results: We found that PRMT2 expression was significantly upregulated in cardiac endothelial cells following pressure overload. Endothelial-specific silencing of PRMT2 markedly attenuated cardiac hypertrophy, fibrosis, and endothelial phenotypic transition in TAC mice. In vitro, PRMT2 knockdown in isolated murine cardiac microvascular endothelial cells alleviated TGF-β1-induced endothelial phenotypic transition, while PRMT2 overexpression exacerbated these phenotypic changes. Mechanistically, PRMT2 enhanced endothelial phenotypic transition by promoting monomethylation of Snail1 and activation of the Snail signaling pathway. Importantly, endothelial-specific knockdown of Snail1 reversed the phenotypic transition induced by PRMT2 overexpression.

Conclusion: These findings identify PRMT2 as a key epigenetic regulator of endothelial phenotypic transition in cardiac remodeling, suggesting it may serve as a potential therapeutic target for heart failure.