Forum: role of oxidation in atherosclerosis
Glycoxidation and lipoxidation in atherogenesis

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Abstract

Atherosclerosis may be viewed as an age-related disease initiated by nonenzymatic, chemical reactions in a biological system. The peroxidation of lipids in lipoproteins in the vascular wall leads to local production of reactive carbonyl species that mediate recruitment of macrophages, cellular activation and proliferation, and chemical modification of vascular proteins by advanced lipoxidation end-products (ALEs). The ALEs and their precursors affect the structure and function of the vascular wall, setting the stage for atherogenesis. The increased risk for atherosclerosis in diabetes may result from additional carbonyl production from carbohydrates and additional chemical modification of proteins by advanced glycation end-products (AGEs). Failure to maintain homeostasis and the increase in oxidizable substrate (lipid) alone, rather than oxidative stress, is the likely source of the increase in reactive carbonyl precursors and the resultant ALEs and AGEs in atherosclerosis. Nucleophilic AGE-inhibitors, such as aminoguanidine and pyridoxamine, which trap reactive carbonyls and inhibit the formation of AGEs in diabetes, also trap bioactive lipids and precursors of ALEs in atherosclerosis. These drugs should be effective in retarding the development of atherosclerosis, even in nondiabetic patients.

Introduction

Atherosclerosis is a chronic disease initiated by retention of lipoproteins in the vascular wall. The deposition of lipoproteins may derive from a number of sources, including alterations in lipoprotein structure and/or size, such as the association of small, dense LDL with development of macrovascular disease [1]. Lipoproteins may also aggregate spontaneously in response to shear stresses or enzymatic modification [2]. It is not the accumulated lipids or aggregated lipoproteins per se, but the peroxidation of lipids in the vascular wall that is implicated in atherogenesis. Bioactive lipids formed during oxidation of lipoproteins induce cellular activation and proliferation [3], [4]. They also degrade to reactive carbonyl compounds that react with proteins, forming advanced lipoxidation end-products (ALEs), the residual evidence of exposure of proteins to lipid peroxidation reactions [5], [6], [7]. ALEs affect not only the structure and recognition of tissue proteins, including lipoproteins, but also modify the charge, hydrophobicity, and elasticity (cross-linking) of the extracellular matrix of the vascular wall. The additional accumulation of advanced glycation end-products (AGEs) in tissue proteins [8] is a likely source of the increased risk for macrovascular disease in diabetes.

The purpose of this article is to discuss the evidence that the chemistry of lipids and carbohydrates, expressed in the form of advanced lipoxidation and glycoxidation reactions, is a major factor in the pathogenesis of atherosclerosis. From the viewpoint that aging is the result of chronic, cumulative chemical modification of proteins and other biomolecules, we propose that atherosclerosis is an age-related disease characterized by accelerated lipid peroxidation and lipoxidative aging of proteins in the vascular wall. We will focus on the role of increased substrate concentration in blood (hyperlipidemia) in the pathogenesis of atherosclerosis and on the mechanisms by which diabetes, which is characterized by disturbances in both carbohydrate and lipid metabolism, is an independent risk factor for the development of vascular disease.

Section snippets

Chemical damage during aging

Life is a highly regulated biological process, and aging may be viewed as the counterprocess by which random chemical reactions gradually degrade the performance of the biological system. Death, in this context, results from the gradual dominance of chemical entropy over the biological order of the living system. Were it not for sophisticated genomic control mechanisms and expenditure of energy, our biological system would collapse at any time and, under sterile conditions, purely chemical

Substrate-induced aging

Measurements of plasma metabolite, enzyme, or protein concentrations are useful for the diagnosis and management of disease. An increase in plasma glucose or lipid concentration is also indicative of, or a risk factor for, chronic age-related diseases. Hyperlipidemia is a significant risk factor for development of macrovascular disease, and hyperglycemia is the major risk factor for a range of diabetic complications. It is irrelevant whether the increase in plasma lipids and/or carbohydrates is

ALEs, AGEs, and BAGLEs

In atherosclerosis, the process of lipoxidation, the chemical modification of protein by products of lipid peroxidation reactions, begins with the formation of lipid peroxides containing conjugated dienes. Lipid peroxides may be formed by enzymatic (lipoxygenase) or nonenzymatic (metal-catalyzed) mechanisms, or by both, such as the enzymatic formation of hydrogen peroxide, followed by metal-catalyzed peroxidation. The role of free metal ions in lipid peroxidation in vivo is disputed, but it is

Pathogenic significance of ALEs, AGEs, and EAGLEs

The toxic species formed during nonenzymatic chemistry include not only the end-products—ALEs, AGEs, and EAGLEs—but also the soluble, reactive intermediates in their formation. Precursors, such as MGO, MDA, and HNE are cytotoxic [15], and isoprostanes formed during lipid peroxidation mimic many of the biological properties of natural prostanoids [4]. ALE-containing lipoproteins may be either stimulatory [45] or toxic [46] to cells. AGE-proteins (glycoxidized proteins) induce oxidative stress

Conclusions

Considered from the viewpoint of chemical hypotheses on aging and age-related pathologies, atherosclerosis and diabetes are closely related diseases. Abnormalities in lipid concentration and metabolism are associated with insulin resistance [70], an early stage in type 2 diabetes, while diabetes is an independent risk factor for both micro- macro-vascular disease [71]. In this brief overview, we have considered atherosclerosis as an age-related disease whose pathology results, in part, from an

Acknowledgements

Work in the authors’ laboratory was supported by U.S. Public Health Service Grants DK-19971 and POI- HL-55782, and Juvenile Diabetes Foundation Grant JDF-996001.

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    1

    Dr. John Baynes earned his Ph.D. in Physiological Chemistry from Johns Hopkins School of Medicine in 1973 and did postdoctoral research in Clinical Chemistry and Laboratory Medicine at the University of Minnesota. He joined the faculty of the University of South Carolina School in 1976 and is now a Carolina Distinguished Professor.

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    For over 20 years, Drs. Baynes and Thorpe, a husband and wife team, have studied the role of carbohydrates, lipids, and oxidative stress in the chemical modification and cross-linking of proteins during aging and in diabetes and atherosclerosis.

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    Dr. Suzanne Thorpe earned her Ph.D. in Biochemistry from the University of Pittsburgh in 1972 and did postdoctoral research in Medical Genetics at the University of Minnesota. She joined the faculty of the University of South Carolina in 1976 and is now Research Professor of Chemistry and Biochemistry.

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