Abstract Aims Atherosclerosis is mediated by circulating monocytes and lesional macrophages through chronic inflammatory responses with metabolic reprogramming. Since methionine metabolism favors the proinflammatory capacity of monocytes/macrophages, we investigated its role in the pathogenesis of atherosclerosis and its clinical relevance. Methods and Results From 387 patients undergoing pancoronary optical coherence tomography, 38 paired patients with or without vulnerable plaque (thin-cap fibroatheroma TCFA) were enrolled and underwent targeted metabolomics of monocytes methionine metabolism. Increased methionine metabolism was significantly associated with plaque vulnerability. Methionine adenosyltransferase Ⅱ alpha (MAT2A), the key enzyme of methionine metabolism, was highly expressed during atherosclerosis progression in humans and mice. Myeloid cell-specific ablation of MAT2A altered monocytes/macrophages proinflammation and migration, thereby attenuating atherosclerosis. Further epigenetic profiling of inflammatory and migratory gene promoters revealed MAT2A-mediated enrichment of the transcriptional permissive chromatin mark H3K4me3. Blockade of methionine metabolism with a specific MAT2A inhibitor or a low-methionine diet impaired proinflammatory and migratory capabilities of monocytes/macrophages and attenuated plaque vulnerability. Mechanistically, norepinephrine evokes the mTOR-c-MYC axis, which could activate MAT2A expression and promote atherosclerosis. In the validation cohort of 100 paired patients from 845 patients, the combination of norepinephrine and methionine metabolism was significantly associated with the presence of TCFA and 5-year clinical prognosis. Conclusions The methionine metabolic profile of monocytes is associated with plaque vulnerability in patients. MAT2A-mediated methionine metabolism utilizes epigenetic modifications to drive monocytes/macrophages inflammation and migration, thereby inducing plaque vulnerability. Inhibition of MAT2A and methionine metabolism to perturb the proinflammatory and migratory capacities may be a promising strategy to alleviate atherosclerosis.
Du et al. (Sat,) studied this question.