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The renin-angiotensin system (RAS) plays an essential role in fluid and electrolyte homeostasis and the regulation of vascular tone; however, dysregulation and over-activation of the RAS lead to the pathogenesis of various cardiovascular diseases. The RAS is closely associated with NADPH oxidase, a major enzymatic source of reactive oxygen species (ROS) in vasculature, and angiotensin II, the final effecter of the RAS, is a potent stimulator of this oxidase. There are accumulating evidences to support the significance of NADPH oxidase in the pathogenesis of atherosclerosis. We demonstrated that the expression of NADPH oxidase is markedly enhanced in human atherosclerotic coronary arteries, and the distribution of oxidized oxidized low-density lipoprotein (LDL) in vasculature is closely associated with NAPDH oxidase and ROS. Our series of observations indicate there is a vicious circle consisting of vascular NADPH oxidase, the RAS, ROS, and oxidized LDL. Furthermore, we demonstrated that angiotensin II type 1 receptor blockers (ARBs) significantly suppressed the expression of NADPH oxidase p22(phox) in the aortic walls of patients with thoracic aortic aneurysm. ARBs, widely used for treatment of hypertension and hypertension-related organ damage, have succeeded in reducing the onset of cardiovascular diseases, preventing organ damage, and cardiac death. These beneficial effects of ARBs are largely dependent upon their primary effects of blood pressure lowering. However, this group of agents exerts a wide variety of biological effects on vascular metabolism, including antioxidative and anti-inflammatory actions. These pleiotropic actions play a role in cardiovascular protection. From a viewpoint of oxidative stress, we discuss pleiotropic effects of ARBs on vascular metabolism focusing on pathogenesis of atherosclerosis-based cardiovascular diseases.

Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia. Statin, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is an inhibitor of cholesterol synthesis. Statin is the first-choice drug to reduce low-density lipoprotein (LDL)-cholesterol for patients with hypercholesterolemia, due to its strong effect to lower the circulating LDL-cholesterol levels. Because a high dose of statins causes concern about rhabdomyolysis, it is sometimes difficult to achieve the guideline-recommended levels of LDL-cholesterol in patients with high LDL-cholesterol treated with statin monotherapy. Ezetimibe has been reported to reduce LDL-cholesterol safely with both monotherapy and combination therapy with statins. Ezetimibe is especially expected to be the best pharmacological option for the treatment of patients unable to achieve LDL-cholesterol goals with statins. Reactive oxygen species (ROS) are produced at low levels to maintain physiological redox balance. Oxidative stress results when ROS production exceeds the ability of cells to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Oxidative stress exacerbates atherosclerosis, the major risk factor for coronary artery disease and ischemic stroke, at every step involves the accumulation of oxidized LDL in the arteries, leading to foam cell formation, plaque development, and plaque rupture. This review focuses on the recent findings of ezetimibe-related atheroprotective effects in vasculature. Moreover, known and proposed mechanisms of how ezetimibe could improve ROS-induced pro-atherosclerotic conditions in vasculature are discussed; these effects may help to explain the mechanisms by which ezetimibe may protect vascular from atherosclerosis.

Prospective epidemiologic studies have shown that dyslipidemia and hyperglycemia are major risk factors for atherosclerotic cardiovascular diseases. Undesirable metabolic conditions are observed to coexist in patients with metabolic syndrome, which is an important risk factor for cardiovascular disease. To prevent cardiovascular disease, a pleiotropic agent is needed to improve the metabolic disorder in patients with metabolic syndrome. Bile acid binding resins increase the fecal excretion of bile acids. The decrease in bile acids returned to the liver leads to an up-regulation of hepatic low-density lipoprotein (LDL) receptor activity, which decreases LDL cholesterol (LDL-C) in the circulation and increases high-density lipoprotein cholesterol. On the other hand, bile acids can also regulate the transcription of genes involved in LDL-C synthesis and cholesterol homeostasis via nuclear hormone receptors. Consequently, these receptors may represent novel therapeutic targets for dyslipidemia and provide insight into the role of the bile acid pathway in other metabolic processes. This review focuses on the recent findings on bile acid binding resins and cardiovascular disease risk factors. Moreover, known and proposed mechanisms of how bile acid binding resins may improve glucose and energy metabolism are discussed; these effects may help to explain the mechanisms by which bile acid binding resins may reduce cardiovascular disease.