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Transition metals redox: reviving an old plot for diabetic vascular disease
Vincent M. Monnier
Case Western Reserve University, Institute of Pathology, Cleveland, Ohio 44106, USA.
Phone: (216) 368-6613; Fax: (216) 368-0495; E-mail: vmm3@po.cwru.edu.
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Published April 1, 2001 - More info
J Clin Invest. 2001;107(7):799–801. https://doi.org/10.1172/JCI12635.
© 2001 The American Society for Clinical Investigation
Considerable effort over the past 25 years has focused on the role of oxidant stress in aging and in the pathogenesis of age-related diseases — diabetes, Alzheimer’s disease, end-stage renal disease, and atherosclerosis, among others. Research on redox signaling and the chemistry of the aging process has led to major insights, including the identification of oxidant stress–responsive transcription factors, such as NF-κB, which regulate tissue remodeling and therefore control the progression of pathological lesions; the role of mitochondria in generating reactive oxygen species and activating apoptotic pathways; the role of sulfhydryl homeostasis in redox signaling; and the development of mass spectrometry methods to identify and quantify protein damage in aging or stressed tissues.
Because of the prevalence and the dire consequences of the diseases involved, the stakes in this field are high. However, despite the great interest in developing drugs that might block oxidant or carbonyl stress, clinical studies involving antioxidant or carbonyl-trapping agents have had mixed success, suggesting a greater degree of complexity than anticipated. Thus, in the diabetic rat, treatment with various antioxidants or carbonyl-trapping agents has had impressive effects in delaying, if not altogether preventing, complications of diabetes such as cataracts, retinopathy, nephropathy, vascular abnormalities, nerve conduction velocity, plasma lipid oxidation, and fetal malformations. In the diabetic human, conversely, while intra-arterial infusion of vitamin C improved endothelium-dependent vasodilation (1) and oral intake of vitamin E improved retinal blood flow and creatinine clearance (2), chronic treatment with vitamin E did not reduce cardiovascular risk (3). Similarly, the antioxidant α-lipoic acid decreased plasma hydroperoxides in diabetic subjects but had equivocal efficacy in polyneuropathy and cardiac autonomic neuropathy (4, 5). A similar “antioxidant paradox” has also been observed in other diseases associated with oxidant stress (6).
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Hydroxyl radicals revisited
Many of the data implicating myeloperoxidase in early atherosclerotic lesions were limited to nondiabetic tissue. In this issue of the JCI, Pennathur et al. (16) have now examined the oxidative chemistry occurring in early atherosclerosis in Cynomologus monkeys after 6 months of streptozotocin-induced diabetes and feeding of a Western-type diet. Working with a protein-rich extract from thoracic aorta, these authors quantified o- and m-tyrosine, o,o′-dityrosine, and 3-nitrotyrosine as markers of damage from hydroxyl radical, myeloperoxidase activity, and peroxynitrite, respectively. They report that o-, m-, and dityrosine, but not 3-nitrotyrosine, are significantly elevated in diabetic aortae, indicating that peroxynitrite is an unlikely source of damage. To test the correlation of the data from these chemical analyses with the extent of hyperglycemia, the authors also quantified glycated hemoglobin. They report that two of the oxidative products, o- and m-tyrosine, are tightly correlated with this physiological parameter, but that dityrosine levels are not, consistent with hydroxyl radical–mediated damage but not with a principle role for myeloperoxidase. They further show that glucose autoxidation does not explain their data. Thus, in all likelihood, redox-active transition metals are involved in this form of atherosclerosis.
Figure 1 summarizes one possible sequence of events that may explain how diabetes initiates atherosclerotic lesions without involving inflammatory cells. First, diabetes-associated hyper- and dyslipidemia are expected to accelerate LDL deposition in the arterial wall, while hyperglycemia promotes the formation of the highly reducing Amadori products in both LDL and collagen. Hyperglycemia also leads to the conversion of methylglyoxal to carboxyethyl-lysine (CEL) (reviewed in refs. 11, 17). All these processes occur nonoxidatively. Oxidation of polyunsaturated fatty acids in LDL, mediated by high glucose-driven superoxide formation by mitochondria and NADH oxidase (18, 19), will yield glyoxal, a potent precursor of N-carboxymethyl-lysine (CML) (17). Indeed, CML has been detected immunochemically in early atheromatous lesions (20). Evidence for the presence of CEL in such lesions is still pending, but it is expected based on findings of elevated CEL in diabetic tissues (17).
Figure 1Proposed sequence of events leading to hydroxyl radical–mediated protein damage in early atherosclerosis in diabetes. The data from Pennathur et al. (16) show a strong relationship between hydroxyl radical damage and hemoglobin glycation. Because these authors found no evidence for increased nitration-mediated damage, it appears that formation of the initial lesion does not involve inflammatory cells. A likely scenario involves increased glycation and the formation of the redox-active center due to the formation of carboxymethyl-lysine (CML) and carboxyethyl-lysine (CEL), which can bind redox-active copper and perhaps iron. Amadori products and ceruloplasmin (not shown) are also expected to be potent precursors of oxidative damage. Hyperglycemia-catalyzed superoxide formation from mitochondrial and cytoplasmic sources is expected to initiate the lipoxidation cascade and release of glyoxal, a potent CML precursor. PUFA, polyunsaturated fatty acid.
The strong relationship observed between glycated hemoglobin and hydroxyl radical damage suggests a concomitant process in which CML originates from Amadori products through hydroxyl radical–mediated oxidation (21). Proteins rich in CML (22) and methylglyoxal-treated proteins (R. Subramaniam and V.M. Monnier, unpublished results) have been found to bind redox-active Cu2+, providing a possible mechanism for the protein damage reported by Pennathur et al. (16). Of major interest in this context is the recent suggestion of Saxena et al. (23) that ascorbic acid, which is also found in atheromatous plaques, can generate CML and become a pro-oxidant in the presence of transition metals.
Still unclear is the exact source of the transition metals. Possibilities include the transfer of loosely bound metals to CML/CEL-rich proteins, which could result from glycation of superoxide dismutase, ceruloplasmin, or ferritin (24), and the possible binding of redox-active iron by Amadori products (25). However, intact ceruloplasmin can also oxidize lipoproteins (26), and its levels are increased in selected patients with diabetes.
The apparent absence of myeloperoxidase- and nitration-mediated oxidation suggests that inflammatory cells are not involved at the very early stage of atherogenesis in diabetes. This scenario may be specific for diabetes, since previous data from apparently nondiabetic individuals suggest the contrary (14). However, once they become oxidized and accumulate CML and other advanced glycation products, vessel-associated LDL and other proteins can act as signals and chemotactic factors for activation of inflammatory cells by binding to RAGE, CD36, or other receptors (27–29). Once that barrier has been crossed, it is not surprising that many forms of protein damage ensue.
If the mechanisms put forward in Figure 1 apply to the early phase of atherosclerosis in diabetes, then therapeutic antioxidants will be needed much earlier in the process than previously appreciated. Transition metal–chelating agents and hydroxyl radical scavengers may prove useful as adjuvants to other forms of therapy.
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