Resveratrol as a Potential Platelet Inhibitor in Aspirin-Resistant Diabetic Patients—A Novel Therapeutic Strategy Targeting F0F1-ATP Synthase Inhibition

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In Diabetes Mellitus (DM), a metabolic disorder characterized by elevated blood glucose due to impaired insulin action, platelet function is dysregulated and contributes to the pathological progression of the disease. In type 2 diabetes mellitus (T2DM), hyperglycemia, insulin resistance, oxidative stress, and inflammation impair endothelial function and platelet regulation, promoting a prothrombotic state. Platelet hyperreactivity is associated with T2DM cardiovascular complications, a leading cause of mortality in patients. Antiplatelet therapies often prove ineffective for a subset of T2DM patients due to aspirin resistance, necessitating alternative therapeutic strategies. Resveratrol, a natural polyphenol, is a potential therapeutic agent for T2DM, including inhibition of platelet aggregation. One of the pleiotropic actions of resveratrol is to modulate the FoF1-ATP synthase rotational catalysis. Platelet chemical energy demand during the activation phase is achieved through oxidative phosphorylation. Both mitochondrial and extra-mitochondrial oxidative phosphorylation drive aerobic energy production in activated platelets, utilizing fatty acids and glucose, respectively. Hyperglycemia can cause an overwork of the oxidative phosphorylation, producing oxidative stress. Targeting FoF1-ATP synthase with resveratrol may reduce platelet hyperreactivity in aspirin-resistant cases. This paper reviews the implications of resveratrol ability to inhibit platelet FoF1-ATP synthase on its potential as a novel alternative or synergistic antiplatelet strategy for aspirin-resistant T2DM patients.