Dihydromyricetin Attenuates Platelet Hyperactivity in HFD/STZ-Induced Diabetic Mice by Inhibiting Intraplatelet ROS Generation

Abstract

The interaction between polyphenols and platelets is an emerging area in understanding how diet affects heart disease. Platelet hyperactivity is one of critical drivers of cardiovascular complications in Type 2 diabetes mellitus (T2DM). As one of the abundant polyphenols in nature, dihydromyricetin (DHM) has been shown to inhibit platelet activation and aggregation in vitro. This study aimed to investigate the in vivo effects and potential mechanisms of dietary DHM supplementation on platelet hyperactivity in diabetic mice. T2DM mouse model was established by feeding a high-fat diet (HFD) combined with streptozotocin (STZ) injection, followed by dietary supplementation with DHM (500 or 1000 mg/kg in diets) for eight weeks. Flow cytometric analysis revealed that DHM significantly reduced platelet surface expression of CD62P, CD63, and CD40 ligands, decreased integrin αIIbβ3 activation, and suppressed intraplatelet reactive oxygen species (ROS) production. The exaggerated platelet aggregation and ATP secretion induced by thrombin and collagen were also markedly attenuated. Additionally, DHM reduced plasma levels of in vivo platelet activation markers, soluble P-selectin, platelet factor 4, thromboxane B2, and the oxidative stress marker 8-iso-prostaglandin F2α. DHM administration also delayed collagen/epinephrine-induced pulmonary embolism formation without prolonging tail bleeding time in T2DM mice. Molecular docking suggested binding interactions between DHM with NADPH oxidase-2, aldose reductase, and platelet receptor PAR 1, GPVI, as well as COX 1. Collectively, dietary DHM attenuated platelet hyperactivity and thrombus formation in T2DM mice, primarily through suppression of intraplatelet ROS formation. These findings highlight DHM as a promising natural candidate for preventing diabetic cardiovascular complications.