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

Figures

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  Figure 1. Chemical structure and mechanisms of resveratrol in platelet hyperactivation. Resveratrol (RSV), a natural polyphenol found in grapes, peanuts, and berries, exerts antioxidant and anti-inflammatory effects through activation of SIRT1, AMPK, and Nrf2 pathways. It enhances endothelial protection by stimulating nitric oxide synthase (eNOS) and prostacyclin (PGI2) release. RSV inhibits platelet adhesion by interfering with von Willebrand factor (vWF) binding to GPIb, and reduces platelet aggregation by suppressing cyclooxygenase-1 (COX-1)–mediated thromboxane A2 (TXA2) formation. Importantly, RSV directly modulates mitochondrial and ectopic F0F1-ATP synthase, reducing excess ATP production and oxidative stress, thereby attenuating platelet hyperreactivity.

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  Figure 2. Platelet metabolism in type 2 diabetes mellitus (T2DM) and resveratrol inhibition of ATP synthase. (Left panel) In T2DM, increased glucose uptake and glycolysis lead to excessive pyruvate availability, fueling mitochondrial oxidative phosphorylation (OxPhos) via the F0F1-ATPase complex. This results in excessive ATP and reactive oxygen species (ROS) production, contributing to platelet hyperreactivity and aspirin resistance (AR). (Right panel) Resveratrol directly interacts with the ATP synthase complex, reducing OxPhos activity, ATP output, and ROS generation. This inhibition attenuates platelet hyperreactivity and counteracts AR, highlighting its potential as an adjunct antiplatelet therapy in diabetes. The structural model of ATP synthase (PDB: 2JIZ) is shown, with a magnified view illustrating key amino acid residues predicted to interact with resveratrol.