Comparative Efficacy of Curcumin and Its Metabolite Tetrahydrocurcumin in Attenuating Diabetic Platelet Hyperreactivity by Suppressing Integrin αIIbβ3 Activation via an Oxidative Stress-Dependent Pathway

Platelet hyperreactivity significantly contributes to the thrombotic risk in type 2 diabetes (T2DM). This study compared the effects of curcumin (CUR) and its intestinal metabolite tetrahydrocurcumin (THC) on diabetic platelet hyperreactivity using a high-fat diet/streptozotocin-induced T2DM mouse model and high glucose (HG)-stimulated human platelets. Dietary THC supplementation (800 mg/kg diet) for 4 weeks ameliorated metabolic parameters and attenuated platelet hyperreactivity (reduced aggregation and activation) in diabetic mice, showing superior efficacy to CUR. Mechanistically, THC demonstrated superior efficacy in suppressing intraplatelet ROS generation, p53 phosphorylation, and integrin αIIbβ3 activation. In vitro, THC (0.5-10 μM), but not CUR at equivalent concentrations, significantly inhibited HG-induced platelet hyperreactivity. Pharmacological inhibition assays further confirmed that THC's effects were mediated via aldose reductase downregulation, resulting in suppression of ROS-dependent p53 phosphorylation and subsequent αIIbβ3 activation. These findings indicate that THC alleviates diabetic platelet hyperreactivity via an oxidative stress-dependent pathway, suggesting its potential in protecting against hyperglycemia-associated atherothrombosis.