EXT1 in cardiomyocytes promotes heparan sulphate-dependent accumulation of macrophage-derived SOD2 to protect against post-myocardial infarction injury.

BACKGROUND AND PURPOSE: Myocardial infarction (MI) triggers extracellular matrix (ECM) remodelling and oxidative stress, leading to cardiomyocyte injury and adverse cardiac remodelling. Heparan sulphate (HS), a major ECM component, plays an important role in regulating cell-cell communication and stress responses. Exostosin-1 (EXT1), a glycosyltransferase essential for HS biosynthesis, is highly expressed in cardiomyocytes, yet its role in post-MI repair remains incompletely understood. EXPERIMENTAL APPROACH: We investigated the role of cardiomyocyte EXT1 in myocardial ischaemic injury using genetic and pharmacological approaches in vitro and in vivo. KEY RESULTS: Cardiomyocyte-specific Ext1 silencing exacerbated infarct size, mitochondrial abnormalities, oxidative stress and fibrosis following permanent left anterior descending coronary artery ligation, whereas EXT1 preserved mitochondrial integrity and redox balance under hypoxic stress. Mechanistically, infiltrating macrophages released superoxide dismutase 2 (SOD2), and myocardial accumulation of macrophage-derived SOD2 was reduced after EXT1 depletion or HS disruption. HS disruption impaired SOD2 accumulation and worsened ischaemic injury, while pharmacological activation of macrophages with dimethyl itaconate (DMI) enhanced SOD2 release and conferred cardioprotection in an EXT1-dependent manner. CONCLUSIONS AND IMPLICATIONS: These findings identify cardiomyocyte EXT1 as a regulator of HS-dependent macrophage-cardiomyocyte crosstalk that limits oxidative damage and adverse remodelling after MI. They further suggest that modulation of the EXT1-HS axis, including pharmacological enhancement of macrophage antioxidant signalling by DMI, may represent a strategy to reinforce endogenous cardioprotection after ischaemic injury.