Coenzyme Q10 Mitigates Myocardial Infarction by Modulating HDAC4 O‐ GlcNAcylation

Myocardial infarction (MI) is a major cause of mortality. This study explores the cardioprotective effects of Coenzyme Q10 (CoQ10) and its molecular mechanisms in MI. A rat myocardial ischemia-reperfusion model was established, and infarct size was assessed via triphenyl tetrazolium chloride (TTC) staining. Hematoxylin and eosin (H&E) and Masson's staining analyzed histological changes, while terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and flow cytometry assessed apoptosis. Western blot and immunofluorescence evaluated collagen I, collagen III, α-SMA, histone deacetylases (HDACs) (4,5,7,9,11), O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and O-GlcNAcylation. Enzyme-linked immunosorbent assay (ELISA) measured tumor necrosis factor (TNF)-α, interleukin (IL)-6, transforming growth factor (TGF)-β, suppression of tumorigenicity (ST)-2, galectin (Gal)-3, and growth differentiation factor (GDF)-15, while cell counting kit-8 (CCK-8), EdU, and Transwell migration assays assessed fibroblast proliferation and migration. O-GlcNAcylation of HDAC4 was analyzed using Click-iT labeling and immunoprecipitation. Cycloheximide chase assay and ubiquitination assay detected the impact of O-GlcNAcylation at Ser455 on HDAC4 protein stability. CoQ10 significantly improved cardiac function in rat models, reducing infarct size, apoptosis, fibrosis, and inflammation. CoQ10 treatment in MIRI rats increased ejection fraction (EF) and fractional shortening (FS), reduced infarct volume (TTC staining), and decreased collagen deposition (Masson's, Sirius Red staining). TUNEL and flow cytometry confirmed reduced cardiomyocyte apoptosis, while ELISA showed lower TNF-α, IL-6, and TGF-β, indicating suppressed inflammation. At the molecular level, CoQ10 reduced global O-GlcNAcylation together with decreased OGT and increased OGA expression. Western blot and immunofluorescence confirmed reduced HDAC4 levels, linked to O-GlcNAcylation suppression particularly at Ser455. CoQ10 promoted the degradation of HDAC4 through the precise inhibition of its stabilizing O-GlcNAc modification at Ser455. In vitro, CoQ10 enhanced oxygen-glucose deprivation and reperfusion (OGD/R) cardiomyocyte survival, reduced apoptosis (TUNEL, flow cytometry), and suppressed HDAC4 expression. In fibroblasts, CoQ10 inhibited TGF-β1-induced proliferation/migration (CCK-8, EdU, Transwell assays) and reduced collagen I, collagen III, and α-SMA expression, indicating anti-fibrotic effects. Furthermore, HDAC4 knockdown in vivo improved cardiac function, and in vitro reduced cardiomyocyte apoptosis and fibroblast proliferation/migration, reinforcing HDAC4's role in MI pathology. CoQ10 exerts cardioprotective effects by modulating O-GlcNAc modification and HDAC4 expression.