The Jeremiah Metzger Lecture. Pathogenesis of atherosclerosis: redox as a unifying mechanism.
Excessive production of reactive oxygen species (ROS) occurs in many diseases and oxidation may be a common disease mechanism generally. The original "oxidation hypothesis" concerning the pathogenesis of atherosclerosis was posited in the context of the putative central role of oxidized LDL in the process. Atherosclerosis has three major characteristic features: inflammation with accumulation of T-cells and, in particular, monocytes, which become lipid rich foam cells; remodeling of the arterial wall; and the non-random localization of lesions to areas of disturbed flow or of low shear stress. The evidence is reviewed that each of these characteristics can be attributed to excessive ROS, which are derived from cellular oxidases, especially, the NAD(P)H oxidases. This expanded concept of the central role of oxidation in the pathogenesis of atherosclerosis has led to a renewed and intense interest in the potential role of antioxidants in therapy. The vascular protective effects of existing drugs such as statins and ACE inhibitors that are not related to serum lipid alterations are attributed to their indirect but effective roles as antioxidants. These data as well as evidence that newly developed antioxidant drugs show promise, not only in experimental animals but also clinically, are reviewed.
Alexander
R Wayne
RW
Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA. ralexan@emory.edu
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015870:Gene Expression; D006439:Hemodynamics; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology
D000975:Antioxidants; D000960:Hypolipidemic Agents; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1