Protein arginine methyltransferases in cardiovascular disease: mechanisms, therapeutic potential, and future directions

Figures

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  Figure 1. Schematic representation of protein arginine methylation pathways and PRMT isoform specificity. Free protein arginine residues undergo initial monomethylation to form monomethylarginine (MMA) by all types of protein arginine methyltransferases (PRMTs), utilizing S-adenosylmethionine (SAM) as the methyl donor and generating S-adenosylhomocysteine (SAH) as a byproduct. MMA serves as a transient intermediate that can be sequentially modified. Type I PRMTs (PRMT1, 2, 3, 4, 6, and 8) catalyze subsequent asymmetric dimethylation to produce asymmetric dimethylarginine (ADMA), whereas Type II PRMTs (PRMT5 and 9) catalyze symmetric dimethylation to form symmetric dimethylarginine (SDMA). In contrast, Type III PRMT (PRMT7) functions exclusively to generate MMA as its final product and does not catalyze further dimethylation reactions.

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  Figure 2. The PRMT-DDAH-ADMA axis in cardiovascular disease. Type I PRMTs methylate protein arginine residues using S-adenosylmethionine (SAM) as the methyl donor, producing methylated proteins and S-adenosylhomocysteine (SAH). Proteolysis of methylated proteins releases free asymmetric dimethylarginine (ADMA), which competitively inhibits nitric oxide synthase (NOS), thereby reducing NO production. DDAH1 and DDAH2 enzymes metabolize ADMA to citrulline and dimethylamine, thereby preventing NOS inhibition. Dysregulation of this pathway leads to endothelial dysfunction, vasoconstriction, platelet aggregation, and atherosclerosis.

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  Figure 3. Cell-type specific roles of PRMTs in cardiovascular remodeling. This schematic summarizes the major arginine methyltransferase–dependent pathways in key cardiovascular cell types. In endothelial cells, PRMT1 increases ADMA, which inhibits endothelial nitric oxide synthase (eNOS), leading to reduce NO production and impaired angiogenesis. DDAH1/2 degrade ADMA, thereby restoring NO bioavailability and angiogenic capacity. In vascular smooth muscle cells, PRMT5-mediated histone methylation drives phenotypic switching from a contractile to a synthetic state, contributing to vascular remodeling. In cardiomyocytes, PRMT1 regulates CaMKII-dependent calcium handling and SRSF1-mediated splicing, while PRMT7 modulates JAK/STAT and Wnt/β-catenin signaling to limit oxidative stress and hypertrophic responses. PRMT6 promotes hypertrophic transcription through H3R2 methylation. Together, these cell-type specific PRMT actions integrate epigenetic and signaling mechanisms that shape cardiac and vascular remodeling in cardiovascular disease.