Phenylacetyl glutamine (PAGln) enhances cardiomyocyte death after myocardial infarction through β1 adrenergic receptor

Abstract This study aims to explore the roles of phenylacetyl glutamine (PAGln) on myocardial infarction (MI) pathogenesis. Here, using targeted metabolomics analysis, it was found that the plasma metabolite PAGln was upregulated in coronary artery disease (CAD) patients and MI mice and could be an independent risk factor for CAD. In vivo and in vitro functional experiments revealed that PAGln pretreatment enhanced MI‐induced myocardial injury and cardiac fibrosis, as evident by the increased infarct size, cardiomyocyte death, and the upregulated expression of cardiac fibrosis markers (Col1a1 and α‐SMA). Combined with RNA‐sequencing analysis and G protein‐coupled receptor (GPCR) inhibitor, we found that the GPCR signaling activation is essential for PAGln‐mediated effects on cardiomyocyte death. Furthermore, drug affinity responsive target stability and cellular thermal shift assay demonstrated that PAGln could interact with β1‐adrenergic receptor (AR). Moreover, β1‐AR blocker treatment indeed extended the cardiac remodeling after PAGln‐enhanced MI. These results suggest that PAGln might be a potential therapeutic target for extending the cardiac remodeling window in MI patients that signals via β1‐AR.