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In the present study, we investigated if 7,4\u2032\u2010dimethoxy\u20103\u2010hydroxyflavone (DMF\u2010OH), a flavonoid\u2010derived PAR4 antagonist, can ameliorate hyperglycaemia\u2010associated endothelial dysfunction, which is a key early event in the pathogenesis of diabetic vasculopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The effects of hyperglycaemia on PAR4 expression and endothelial dysfunction were examined in a streptozotocin\u2010induced diabetic mouse model and in a high glucose\u2010treated human endothelial cell model. The contribution of PAR4 was studied by using selective antagonists and shRNA\u2010mediated knockdown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In diabetic mice, up\u2010regulation of vascular PAR4 was associated with endothelial dysfunction, defined by increases in proinflammatory cytokines, adhesive molecules, macrophage infiltration, oxidative stress and the procoagulant tissue factor. These abnormalities were ameliorated by oral administration of 7,4\u2032\u2010dimethoxy\u20103\u2010hydroxyflavone, a flavonoid\u2010derived PAR4 antagonist. In cultured endothelial cells, high glucose exposure induced PAR4 expression and enhanced Ca<jats:sup>2+<\/jats:sup> responses to PAR4\u2010activating peptide and thrombin, leading to exaggeration of proinflammatory and procoagulant states. The tissue factor\u2010thrombin\u2010PAR4 loop was blockaded by selective PAR4 antagonists and, to a greater extent, by 7,4\u2032\u2010dimethoxy\u20103\u2010hydroxyflavone. The extra benefit of the latter may be attributed to inhibition of reactive oxygen species (ROS)\u2010dependent NF\u2010\u03baB activation, which is required for hyperglycaemia\u2010induced PAR4 and proinflammatory factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our results indicate an important role for hyperglycaemia\u2010induced PAR4 in aggravating diabetic endothelial dysfunction and suggest a novel strategy targeting PAR4 and ROS for treating vascular complications in diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70105","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T04:48:49Z","timestamp":1749703729000},"page":"4592-4610","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["7,4\u2032\u2010dimethoxy\u20103\u2010hydroxyflavone, a protease\u2010activated receptor 4 (PAR4) inhibitor with antioxidant activity, 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