Serum Ceruloplasmin Level and the Risk of Myocardial Infarction and Stroke

Reunanen, Antti; Knekt, Paul; Aaran, Ritva-Kaarina

doi:10.1093/oxfordjournals.aje.a116573

Cited by 112 publications

(67 citation statements)

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“…The role of Cp oxidant activity in inflammation and other pathological processes is not known. The strong association of serum Cp and coronary heart disease (39,40) and the presence of immunodetectable Cp in human atherosclerotic lesions (41,42) are consistent with a role of Cp prooxidant activity in vascular disease progression. The new information on the specific prooxidant site of Cp should permit genetic approaches in which specific functions of Cp are altered in transgenic animals, providing a powerful tool for assessing the normal and pathological function(s) of Cp in vivo.…”

Section: Discussionmentioning

confidence: 65%

Identification of the prooxidant site of human ceruloplasmin: A model for oxidative damage by copper bound to protein surfaces

Mukhopadhyay

Mazumder

Lindley

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

106

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Free transition metal ions oxidize lipids and lipoproteins in vitro; however, recent evidence suggests that free metal ion-independent mechanisms are more likely in vivo. We have shown previously that human ceruloplasmin (Cp), a serum protein containing seven Cu atoms, induces low density lipoprotein oxidation in vitro and that the activity depends on the presence of a single, chelatable Cu atom. We here use biochemical and molecular approaches to determine the site responsible for Cp prooxidant activity. Experiments with the His-specific reagent diethylpyrocarbonate (DEPC) showed that one or more His residues was specifically required. Quantitative Transition metal ions such as Cu and Fe are extremely effective promoters of oxidation reactions and can cause the oxidative modification of low density lipoprotein in vitro (1, 2). The involvement of free metal ions in oxidation processes in vivo has been questioned because most of these ions are linked to prosthetic groups or are tightly sequestered by specific binding proteins, and thus the level of free Cu (and Fe) in plasma and interstitial fluids is extremely low (3). In addition, recent mass spectroscopic analysis suggests that the oxidized lipid ''fingerprint'' exhibited by human atherosclerotic lesions is not consistent with free metal-catalyzed processes (4). In view of these findings, recent attention has focused on the investigation of free metal ion-independent mechanisms, such as those using peroxidases (5, 6), and on metal-binding proteins (7-9), which can promote LDL oxidation.Studies by us (10-12) and others (13)(14)(15) show that the copper protein ceruloplasmin (Cp) exhibits potent oxidant activity toward LDL in vitro. Cp is a plasma glycoprotein containing about seven Cu atoms per molecule and Ϸ95% of the total plasma Cu (see refs. 16 and 17 for review). It is a 132-kDa monomer comprised almost entirely of three major domains that have 35-40% sequence homology to each other (18) and to three homologous domains in factors Va and VIIIa (19).

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Section: Discussionmentioning

confidence: 65%

Identification of the prooxidant site of human ceruloplasmin: A model for oxidative damage by copper bound to protein surfaces

Mukhopadhyay

Mazumder

Lindley

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

106

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“…We previously investigated the risks of several common chronic diseases and serum concentrations of antioxidants and micronutrients in a large prospective population study (Knekt et al, 1988;Knekt et al, 1992;Reunanen et al, 1992;Helio Èvaara et al, 1994). In this report of a nested casecontrol study we analyse the associations between the incidence of NIDDM and levels of b-carotene, retinol and a-tocopherol.…”

Section: Introductionmentioning

confidence: 99%

Serum antioxidants and risk of non‐insulin dependent diabetes mellitus

et al. 1998

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Objective: To examine whether serum levels of a-tocopherol, b-carotene and retinol were associated with risk of non-insulin dependent diabetes mellitus (NIDDM). Design and subjects: The study design was a nested case-control study within a longitudinal population study. Serum levels of antioxidants were determined in 106 incident cases with non-insulin dependent diabetes mellitus detected on follow-up and 201 controls matched for sex, age and study region. Results: The incident cases had lower serum a-tocopherol and b-carotene levels than controls. The relative risk between the highest and lowest tertiles of serum a-tocopherol was 0.61 (95% con®dence interval (CI) 0.32±1.15), between the highest and lowest tertiles of serum b-carotene 0.45 (CI 0.22±0.92). Although the relative risk of highest compared with lowest tertile of serum a-tocopherol was not statistically signi®cant the inverse trend through the tertiles was (P`0.05). The decreasing risk of diabetes was particularly evident in the elderly, women, nonsmokers and the obese. However, adjustment for serum cholesterol, obesity, smoking and hypertension abolished the associations. The adjusted relative risks in relation to serum a-tocopherol and bcarotene (between highest and lowest tertiles) were 1.25 (CI 0.54±2.90) and 0.94 (CI 0.38±2.32), respectively. No associations were observed relating to serum retinol. Conclusions: High levels of a-tocopherol and b-carotene were found to be associated with decreased risk of noninsulin dependent diabetes mellitus, but the association disappeared after adjustment for cardiovascular risk factors.

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“…Plasma ceruloplasmin concentration increases about 10-fold during development and further rises up to threefold during pregnancy and during multiple pathological processes including trauma and inflammation (for review see reference 19). Elevated serum ceruloplasmin has been found to be a risk factor for coronary heart disease (20,21), and a strong correlation exists between serum ceruloplasmin and serum lipid oxidation (22). Ceruloplasmin in human atherosclerotic lesions has been detected (23,24), but the cellular sources responsible for ceruloplasmin accumulation during this and other inflammatory processes are not known.…”

Section: Introductionmentioning

confidence: 99%

Role of endogenous ceruloplasmin in low density lipoprotein oxidation by human U937 monocytic cells.

Ehrenwald¹,

Fox²

1996

J. Clin. Invest.

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Oxidation of lipids and lipoproteins by macrophages is an important event during atherogenesis. Activation of monocytic cells by zymosan and other agonists results in the release of multiple oxidant species and consequent oxidation of LDL. We now show evidence that ceruloplasmin, a copper-containing acute phase reactant, is secreted by zymosan-activated U937 monocytic cells, and that the protein has an important role in LDL oxidation by these cells. In one approach, ceruloplasmin has been shown to exhibit oxidant activity under the appropriate conditions. Exogenous addition of purified human ceruloplasmin stimulates U937 cell oxidation of LDL to nearly the same extent as activation by zymosan. In contrast to previous cell-free experiments (Ehrenwald, E., G. IntroductionActivated monocytes and macrophages are recognized for their remarkable diversity of secreted products, including multiple reactive oxygen and nitrogen intermediates, involved in the injury or killing of invasive organisms such as bacteria, parasites, and tumor cells (1). The same oxidation reactions may also cause secondary oxidative damage to host macromolecules and tissues during chronic inflammatory processes. For example, there is now abundant evidence that particles resembling oxidatively modified LDL are present in atherosclerotic lesions (2). Recent evidence suggests that oxidative damage is a critical factor in disease progression since antioxidants may reduce the onset or severity of cardiovascular disease (3) and inflammatory bowel diseases (4). The mechanisms of cellular oxidation processes have been subjected to intense scrutiny, but despite these efforts the physiological source(s) of transition metals required for metal ion-dependent oxidation reactions is not known (4, 5). A clue to the resolution of this enigma may be found in the observation by Cathcart et al. (6,7) that activated human monocytes, or monocytic cells such as the U937 cell line, oxidize LDL in vitro even in iron and copper ion-free media. This finding distinguishes these cells from endothelial cells and smooth muscle cells that require exogenous copper or iron salts in the medium to achieve optimal oxidation rates (8, 9). One explanation is that monocytic cells may provide their own transition metal ions to maintain high oxidation rates and the inhibition of monocytic cell lipid oxidation by divalent cation chelators is consistent with this idea (10). Alternatively, macrophage-derived hypochlorous acid or nitric oxide may be precursors of highly reactive hydroxyl radicals by metal ion-independent mechanisms (11).We have recently shown that physiological concentrations of purified human ceruloplasmin (200-400 g/ml in healthy adults) increase the oxidation of LDL in vitro by up to 50-fold when measured as thiobarbituric acid-reactive substances (TBARS) 1 (12). Ceruloplasmin is a monomeric, 132-kD acute

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Serum Ceruloplasmin Level and the Risk of Myocardial Infarction and Stroke

Cited by 112 publications

References 0 publications

Identification of the prooxidant site of human ceruloplasmin: A model for oxidative damage by copper bound to protein surfaces

Identification of the prooxidant site of human ceruloplasmin: A model for oxidative damage by copper bound to protein surfaces

Serum antioxidants and risk of non‐insulin dependent diabetes mellitus

Role of endogenous ceruloplasmin in low density lipoprotein oxidation by human U937 monocytic cells.

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