NOS3 and endothelial dysfunction: A growing number of evidence has demonstrated that excessive ROS-mediated metabolic memory leads to a pro-inflammatory milieu and endothelial dysfunction in the aorta.90,236,238 NADPH oxidase 4 (Nox4) and endothelial nitric oxide synthase (eNOS) are involved in mediating transient hyperglycemia-induced vascular ROS generation and are regulated by altered histone methylation.239 An increase in H3K4me1 at the promoters of Nox4 and eNOS was found in endothelial cells in the hyperglycemic state, which antagonized and downregulated H3K9me2 and H3K9me3.