Antioxidants and Atherosclerosis: Animal Studies

Abstract

Atherosclerosis and its clinical sequelae such as myocardial infarction and stroke represent a major source of morbidity and mortality in the developed world, claiming over 960,000 lives annually in the United States alone (1). A wealth of data now links serum cholesterol, in particular low-density lipoprotein (LDL) cholesterol (2) to the development of atherosclerosis. Despite this causative association between LDL cholesterol and atherosclerosis, isolated LDL particles typically fail to demonstrate atherogenic effects in vitro (3). For example, the loading of tissue macrophages with LDL cholesterol is tightly regulated (3). In contrast, the oxidation of LDL lipids is associated with a number of structural changes within LDL that support its unregulated uptake into macrophages leading to foam cell formation, the hallmark of an early atherosclerotic lesion (3,4). In vitro studies also indicate that oxidized LDL (oxLDL) possesses many other proatherogenic properties that are reviewed in detail in Chapter 4. Consistent with an important role for oxLDL in atherosclerosis, its formation has been identified in vivo (5,6). Despite this demonstration that oxLDL occurs in vivo, data directly attributing a causative role of oxLDL in atherosclerosis has been difficult to obtain. This chapter will review available evidence on antioxidants and atherosclerosis from the perspective that oxLDL is an important factor in the atherogenic process. The implications of the “oxidative modification hypothesis” of atherosclerosis with respect to vascular antioxidant status will be reviewed, and animal intervention trials investigating the effect of antioxidant manipulation on atherosclerosis will be discussed.