Zinc supplementation inhibits lipid peroxidation and the development of atherosclerosis in rabbits fed a high cholesterol diet

Jenner, Andrew; Ren, Minqin; Rajendran, Reshmi; Pan, Ning; Huat, Benny Tan Kwong; Watt, F.; Halliwell, Barry

doi:10.1016/j.freeradbiomed.2006.11.024

Cited by 83 publications

(56 citation statements)

References 46 publications

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“…20 Zinc supplementation was also shown to reduce accumulation of cholesterol in the aorta, decrease the average aortic lesion cross-sectional area, and reduce a number of markers of cholesterol and lipid oxidation. 21 These data are consistent with zinc having an antiatherogenic effect, with this postulated to occur via a reduction in iron-catalyzed radical reactions. 21 High zinc concentrations have also been reported to reduce intimal hyperplasia in a rat carotid artery balloon-injury model.…”

supporting

confidence: 64%

Accumulation of Zinc in Human Atherosclerotic Lesions Correlates With Calcium Levels But Does Not Protect Against Protein Oxidation

Stadler

Stanley

Heeneman

et al. 2008

ATVB

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Objective-Oxidized lipids and proteins, as well as decreased antioxidant levels, have been detected in human atherosclerotic lesions, with oxidation catalyzed by iron and copper postulated to contribute to lesion development. Zinc has been postulated to displace iron from critical sites and thereby protect against damage. In this study, metal ion and protein oxidation levels were quantified in human carotid and abdominal artery specimens containing early-to-advanced lesions, to determine whether zinc concentrations correlate inversely with iron levels and protein oxidation. Methods and Results-Metal ions were quantified by EPR and inductively coupled plasma mass spectroscopy. Native and oxidized protein side-chains were quantified by high-performance liquid chromatography. A therosclerosis is a multifactorial disease to which many factors contribute; defining the role of each of these has proved to be problematic. Oxidation, and in particular that of low-density lipoproteins (LDL), has been linked to disease development, 1 although the significance of this process has not been fully established (reviewed 2 ). Previous studies have variously implicated lipoxygenase, peroxynitrite, myeloperoxidase, oxygen radicals, and metal-ions in lesion oxidation (reviewed 2 ). In the case of metal ions, a correlation between iron accumulation and the extent of protein (but not lipid) oxidation has been reported for human lesions. 3 Cholesterol ester and cholesterol accumulation also correlate positively with iron, suggesting that these processes are interlinked. 3,4 These data are consistent with some, but not all, epidemiological studies on the potential links between iron and cardiovascular disease. [5][6][7][8] Zinc ions have been reported to modulate oxidant damage via the displacement of iron and copper from oxidationsensitive sites on erythrocyte membranes, 9 LDL, 10 or liposomes. 11 Epidemiological data indicate that elevated serum zinc levels may be protective against disease. 12 Serum or plasma measurements of zinc in people with established atherosclerosis indicate that low zinc levels are associated with increased disease 13,14 and a postmortem study has reported lower tissue levels of zinc in the abdominal aorta of patients who died of heart disease compared to other causes. 15 In contrast, zinc supplementation of the human diet does not affect the susceptibility of LDL to oxidation ex vivo 16,17 or the concentrations of LDL-cholesterol, total cholesterol, or triglycerides, but has an adverse effect on high-density lipoprotein levels, suggesting that high serum zinc levels may promote disease. 17 Elevated zinc may stimulate the formation of oxidants and inhibit protective enzymes in some cells. 18 Atherosclerotic lesions of cholesterol-fed rabbits contain elevated levels of iron and reduced levels of zinc. 19 -21 Zinc supplementation, via dietary feeding, reduced lesion area despite insignificant changes in lesion zinc concentrations; these changes were ascribed to a displacement of iron by zinc. 20 Zinc supplement...

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supporting

confidence: 64%

Accumulation of Zinc in Human Atherosclerotic Lesions Correlates With Calcium Levels But Does Not Protect Against Protein Oxidation

Stadler

Stanley

Heeneman

et al. 2008

ATVB

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“…50,51 Although zinc is not redox active, zinc supplementation has been shown to reduce oxidative damage. [52][53][54] Zinc has also been observed to have an antiatherosclerotic effect. [55][56][57][58] Epidemiologic studies revealed that zinc was associated inversely with cardiovascular disease.…”

Section: Zincmentioning

confidence: 99%

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Qin

Reszka

Fukai

et al. 2008

Translational Research

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Extracellular superoxide dismutase (ecSOD) is the major extracellular scavenger of superoxide () and a main regulator of nitric oxide (NO) bioactivity in the blood vessel wall, heart, lungs, kidney, and placenta. Involvement of has been implicated in many pathological processes, and removal of extracellular by ecSOD gene transfer has emerged as a promising experimental technique to treat vascular disorders associated with increased oxidant stress. In addition, recent studies have clarified mechanisms that regulate ecSOD expression, tissue binding, and activity, and they have provided new insight into how ecSOD interacts with other factors that regulate vascular function. Finally, studies of a common gene variant in humans associated with disruption of ecSOD tissue binding suggest that displacement of the enzyme from the blood vessel wall may contribute to vascular diseases. The purpose of this review is to summarize recent research findings related to ecSOD function and gene transfer and to stimulate other investigations into the role of this unique antioxidant enzyme in vascular pathophysiology and therapeutics.Oxidative stress induced by superoxide anion ( ) produced in vascular cells is involved in the pathogenesis of cardiovascular and metabolic diseases, including atherosclerosis, 1 ischemia-reperfusion injury, 2 diabetes, 3 hyperlipidemia, 4 and hypertension. 5 Moreover, may also contribute to pulmonary hypertension, 5 erectile dysfunction, 6 cerebral vasospasm, 7 and other disorders associated with vascular dysfunction. Consequently, strategies to reduce levels of have emerged as promising approaches to treating cardiovascular diseases and other conditions associated with enhanced oxidative stress. In mammalian tissues, 3 isoforms of SODs exist: Cu/Zn SOD (SOD1), Mn SOD (SOD2), and extracellular SOD (ecSOD or SOD3). SOD1 is an abundant copper-and zinc-containing cellular protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial inner membrane. Its primary function is to lower the intracellular steady-state concentration of . SOD1 mutations are associated with neural diseases such as amyotrophic lateral sclerosis. 8 SOD2 is a mitochondrial enzyme that disposes of generated by respiratory chain activity. SOD2 can be induced to protect against prooxidant insults. Conversely, SOD2 activity is decreased in physiologic aging and in diseases such as progeria, cancer, asthma, and transplant rejection. 9 ecSOD, another copper-and zinc-containing dismutase, is a primary antioxidant enzyme secreted to the extracellular space. ecSOD is expressed highly in selected tissues, including blood vessels, heart, lungs, kidney, placenta, and extracellular fluids. ecSOD plays an important role in regulating blood pressure and vascular contraction, at least in part, through modulating the endothelial function by controlling the levels of extracellular and nitric oxide bioactivity in the vasculature. 10,11 ecSOD has also been proposed to play an important role in neurologic, pulmonary, and arthriti...

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“…Free radical mediated oxidation of cholesterol in the 5,6 position forms 7β-hydroxycholesterol (7β-OHC) and 7-ketocholesterol (7-KC). An elevation of these cholesterol oxidation products (COPs) has been reported in several diseases and pathological models that involve oxidative stress [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Kreilaus

Spiro

Hannan

et al. 2015

JHD

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. (2015). Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington's disease: a targeted GC-MS/MS sterol analysis. Journal of Huntington's Disease, 4 (4), 305-318.Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington' s disease: a targeted GC-MS/MS sterol analysis AbstractBackground:Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood. Objective:This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease. We also aimed to characterise the progression of the physical phenotype in these mice. Methods:GC-MS/MS was used to quantify a broad range of sterols in the striatum and cortex of R6/1 and wild type mice at 6, 12, 20, 24 and 28 weeks of age. Motor dysfunction was assessed over 28 weeks using the RotaRod and the hind-paw clasping tests. Results:24(S)-Hydroxycholesterol and 27-hydroxycholesterol were the major cholesterol metabolites that significantly changed in R6/1 mice. These changes were specifically localised to the striatum and were detected at the end stages of the disease. Cholesterol synthetic precursors (lathosterol and lanosterol) were significantly reduced in the cortex and striatum by 6 weeks of age, prior to the onset of motor dysfunction, as well as the cognitive and affective abnormalities previously reported. Elevated levels of desmosterol, a substrate of delta(24)-sterol reductase (DHCR24), were also detected in R6/1 mice at the end time-point. Female R6/1 mice exhibited a milder weight loss and hind paw clasping phenotype compared to male R6/1 mice, however, no difference in the brain sterol profile was detected between sexes. Conclusion:Several steps in cholesterol biosynthetic and metabolic pathways are differentially altered in the R6/1 mouse brain as the disease progresses and this is most severe in the striatum. This provides further insights into early molecular mediators of HD onset and disease progression and identifies candidate molecular targets for novel therapeutic approaches.

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Zinc supplementation inhibits lipid peroxidation and the development of atherosclerosis in rabbits fed a high cholesterol diet

Cited by 83 publications

References 46 publications

Accumulation of Zinc in Human Atherosclerotic Lesions Correlates With Calcium Levels But Does Not Protect Against Protein Oxidation

Accumulation of Zinc in Human Atherosclerotic Lesions Correlates With Calcium Levels But Does Not Protect Against Protein Oxidation

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

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