ROS in Atherosclerosis: What We Know?

Atherosclerosis remains a leading cause of morbidity and mortality worldwide. Reactive oxygen species (ROS), a group of highly reactive molecules, play a critical role in the complex pathogenesis of atherosclerosis. Many risk factors for atherosclerosis including diabetes mellitus, hyperlipidemia, smoking, hypertension, obesity, air pollution, inflammatory bowel disease, and chronic infections are associated with excessive ROS. While ROS act as important signaling molecules in both physiological and pathological conditions, excessive ROS promote oxidative stress, lipid peroxidation, macrophage activation, inflammation, endothelial dysfunction, and vascular remodeling, leading to atherosclerosis. ROS including superoxide anions (O2•−) and hydrogen peroxide (H2O2) are generated through various enzymatic and non-enzymatic pathways locally and systematically. Antioxidant therapy, while conceptually appealing, has yielded mixed results in clinical trials. Vitamins C and E, once thought to be promising antioxidants, have no significant cardiovascular benefits. NADPH oxidases (NOX), particularly NOX2 and NOX4 isoforms, have emerged as significant contributors to ROS production in atherosclerotic lesions. Selective suppression of NOX exhibits a considerable beneficial potential in attenuation of atherosclerosis in preclinical studies. With better understanding of the mechanisms contributing to ROS generation and ROS-mediated endothelial damages/dysfunction, it is predicted that development of new selective ROS-modulating agents will lead to effective personalized preventive and/or treatment strategies for atherosclerosis.