(i) Decreases p66Shc overexpression induced by hyperglycemia; p66Shc promotes oxidation of several targets in the EC mitochondria, thus contributing to endothelial dysfunction. Resveratrol leads to AMPK activation, eNOS increment, reduction of ROS generation and plaque deposition, culminating in improved EC function. (ii) Inhibit the induction of the mitochondrial permeability transition leading to the prevention of EC apoptosis and endothelial loss of function. (iii) Activates PGC-1α, leading to improved mitochondrial biogenesis in EC, thus contributing to improve endothelial dysfunction. The gene discussed is NOS3; the disease is Hyperglycemia.