Are ACE Inhibitors a “Magic Bullet” Against Oxidative Stress?

The recently published Heart Outcomes Prevention Evaluation (HOPE) study,1,2 as well as the Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE),3 demonstrated that treatment with an ACE inhibitor but not vitamin E had beneficial effects on the prognosis and progression of atherosclerosis. In these studies, long-term ACE inhibition significantly reduced the rate of death, myocardial infarction, and stroke and reduced the intima-to-media ratio of carotid arteries in patients at high risk for cardiovascular events. It is likely that these findings will have wide-ranging implications for the treatment of cardiovascular disease, and the contrasting results with respect to ACE inhibitors and vitamin E provide an opportunity to revisit the role of oxidative stress in vascular disease. LDL Oxidation and Cardiovascular DiseaseA surprising finding of these studies was the ineffectiveness of vitamin E in preventing the clinical manifestations of coronary artery disease and the progression of atherosclerosis. A wealth of previous experimental and epidemiological data suggested that excess LDL oxidation was, in part, responsible for the development of atherosclerosis.4 Because vitamin E can inhibit LDL oxidation ex vivo, a logical strategy to reduce oxidative stress would include the administration of antioxidants such as vitamin E. This approach carries considerable risk if the antioxidant is not active against all oxidants relevant to atherosclerosis. Although vitamin E effectively scavenges lipid peroxyl radicals, it has limited activity against other oxidants such as superoxide, peroxynitrite, and hypochlorous acid that have been implicated in atherosclerosis. Another risk with an antioxidant strategy relates to putative cellular compartments or “microdomains” in the vascular wall that do not contain appreciable amounts of the antioxidant. The sum total of these effects would be continued oxidation even in the presence of the antioxidant. Experimental evidence from both animals and patients suggests that lipid peroxidation does proceed …