Site-Specific Antioxidative Therapy for Prevention of Atherosclerosis and Cardiovascular Disease

Figure 1

Strategy of the site-specific antioxidative therapy to prevent cardiovascular disease. The visceral adipose tissues are the primary source of proinflammatory cytokines that impose oxidative stress on endothelial cells (ECs) and cardiomyocytes (CMCs) through activation of NADPH oxidase (Nox) and generation of reactive oxygen species (ROS). Oxidative stress to ECs and CMCs then activates xanthine oxidase (XO) that potentiates the generation of ROS and increases oxidative stress to ECs and CMCs. Oxidative stress to ECs and CMCs causes uncoupling of nitric oxide synthase (NOS) through oxidation and depletion of BH₄ that further increases oxidative stress to ECs and CMCs, creating a self-perpetuating cycle for oxidative stress in ECs and CMCs, leading to the development of cardiovascular disease. Calorie restriction (CR) or regular endurance exercise reduces the mass of the visceral adipose tissue, thereby decreasing the production of proinflammatory cytokines responsible for oxidative stress to ECs and CMCs. Angiotensin converting enzyme (ACE) inhibitors, angiotensin type 1 receptor blockers (ARBs), or statins prevents activation of Nox and mitigates oxidative stress to ECs and CMCs. Allopurinol or oxypurinol blocks XO, while tetrahydrobiopterin (BH₄) or sepiapterin prevents uncoupling of NOS, thereby attenuating oxidative stress to ECs and CMCs. Another important source of ROS within ECs and CMCs is the electron transfer chain (ETC) in mitochondria. Aging, excess feeding, sedentary lifestyle, or hypoxia increases the leakage of electrons from the ETC and generation of ROS that imposes oxidative stress on ECs and CMCs. CR and exercise are a fundamental approach to prevent oxidative stress to ECs and CMCs by reducing the leakage of electrons from the ETC and ROS production. Resveratrol mimics the action of CR and exercise, thereby ameliorating oxidative stress to ECs and CMCs. Peroxisome proliferator-activated receptor (PPAR) α or γ agonists induce activation of uncoupling proteins in mitochondria, thereby reducing the leakage of electrons from the ETC and ROS production. ARBs and statins act as the partial agonists of PPARs that may be related to their preferable cardiovascular effects.