NOS3 and Hyperglycemia: In response to hyperglycemia and hyperlipidemia, the mitochondria-related ROS generation acts as a common upstream event, initiating a plethora of responses converging into multiple pathogenic mechanisms as autophagy, NADPH-oxidases, and uncoupled endothelial nitric oxide synthase (eNOS) induction, causing nuclear DNA double-strand breaks, PARP activation, and apoptotic mechanisms [13,49].