The interaction between ruptured erythrocytes and low&amp;#x2010;density lipoproteins

Paganga, George; Rice‐Evans, Catherine; Rule, Rebecca A.; Leake, David S.

doi:10.1016/0014-5793(92)80508-e

Cited by 65 publications

(5 citation statements)

References 36 publications

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“…Besides classical reactive oxygen metabolites, organic peroxides were shown to induce the leakage of Hb from human erythrocytes [40] and the generation of metHb [41]. FerrylHb generation was detected in the interaction between ruptured erythrocytes and LDL [42, 43]. Parallel with these findings here we showed that oxLDL but not native LDL caused Hb oxidation and subsequent covalent crosslinking of Hb subunits (Figure 4.)…”

Section: Discussionsupporting

confidence: 81%

Atherogenesis May Involve the Prooxidant and Proinflammatory Effects of Ferryl Hemoglobin

Potor

Bányai

Becs

et al. 2013

Oxidative Medicine and Cellular Longevity

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Oxidized cell-free hemoglobin (Hb), including covalently cross-linked Hb multimers, is present in advanced atherosclerotic lesions. Oxidation of Hb produces methemoglobin (Fe3+) and ferryl hemoglobin (Fe4+ = O2−). Ferryl iron is unstable and can return to the Fe3+ state by reacting with specific amino acids of the globin chains. In these reactions globin radicals are produced followed by termination reactions yielding covalently cross-linked Hb multimers. Despite the evanescent nature of the ferryl state, herein we refer to this oxidized Hb as “ferryl Hb.” Our aim in this work was to study formation and biological effects of ferrylHb. We demonstrate that ferrylHb, like metHb, can release its heme group, leading to sensitization of endothelial cells (ECs) to oxidant-mediated killing and to oxidation of low-density lipoprotein (LDL). Furthermore, we observed that both oxidized LDL and lipids derived from human atherosclerotic lesions trigger Hb oxidation and subsequent production of covalently cross-linked ferrylHb multimers. Previously we showed that ferrylHb disrupts EC monolayer integrity and induces expression of inflammatory cell adhesion molecules. Here we show that when exposed to ferrylHb, EC monolayers exhibit increased permeability and enhanced monocyte adhesion. Taken together, interactions between cell-free Hb and atheroma lipids engage in a vicious cycle, amplifying oxidation of plaque lipids and Hb. These processes trigger EC activation and cytotoxicity.

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Section: Discussionsupporting

confidence: 81%

Atherogenesis May Involve the Prooxidant and Proinflammatory Effects of Ferryl Hemoglobin

Potor

Bányai

Becs

et al. 2013

Oxidative Medicine and Cellular Longevity

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“…Most of them including our team have shared common findings of lowered total cholesterol, LDL-C, HDL-C [27, 34–39]. Values from our B-TM patients and many other researchers showed elevated triglyceride levels (TG) [33, 34, 36–38], while others described TG levels as being not- significantly different from controls [35, 39]. CAIMT in the present study was positively correlated with S. TG and atherogenic index of plasma.…”

Section: Discussionmentioning

confidence: 90%

“…Lipid profiles have been described by several investigators but with conflicting results [26, 33–36]. Most of them including our team have shared common findings of lowered total cholesterol, LDL-C, HDL-C [27, 34–39].…”

Section: Discussionmentioning

confidence: 98%

“…Dyslipidemia in thalassemia patients has been previously explained by several researchers who speculated different pathophysiologic pathways; plasma dilution because of anemia, accelerated erythropoiesis with excess cholesterol uptake by macrophages and histocytes of the reticuloendothelial system, defective liver synthetic function because of iron overload, macrophage activation with cytokine release and hormonal disturbance [33, 40, 41] while reduced extra-hepatic lipolytic activity might be responsible for the increased TG in B-TM patients [33]. …”

Section: Discussionmentioning

confidence: 99%

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Premature atherosclerosis in children with beta-thalassemia major: New diagnostic marker

et al. 2017

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BackgroundEarly vascular alteration, atherosclerosis and coronary artery disease have emerged as important cardiovascular complications among beta-thalassemia major (B-TM) patients. The aims of the current study were to assess the prevalence of premature atherosclerosis among our B-TM patients, and to investigate the diagnostic value of serum Osteoprotegerin assay as an early biomarker for atherosclerosis.MethodsThis cross-sectional study was conducted at Hematology unit - Pediatric Department, Zagazig University Children Hospital- Egypt in the period from March 2014 to March 2015. A total of 115 children were enrolled in the current study; as sixty-five (65) children with beta thalassemia major aged 5–18 years, on regular blood transfusion regimen represented the patient group. While fifty (50) healthy children, with comparable age and gender, were assigned as control group. All participants were subjected to history taking, thorough clinical examination and laboratory investigations including; complete blood count, liver and kidney function tests, C- reactive protein, lipid profile, serum ferritin and serum Osteoprotegerin (OPG) assay. Also, carotid artery intima media thickness (CAIMT) was performed by duplex ultrasound for patients and controls.ResultsOur B-TM patients were transfusion-dependent for as long as 8.5 ± 3.8 years with significantly higher serum ferritin levels (2490 ± 1579 ng/dl vs 83 ± 32 ng/dl, p = 0.001), C-reactive protein (5.7 ± 5.7 vs 0.9 ± 0.9), liver enzymes and bilirubin when compared to controls. Significantly higher serum triglyceride (128 ± 20 vs 101 ± 7 mg/dL, p = 0.009) and atherogenic index of plasma (0.45 ± 0.12 vs 0.22 ± 0.04, p = 0.001) were recorded in patients than comparisons. On the contrary, total serum cholesterol (116 ± 16 vs 143 ± 5, p < 0.001), low density lipoprotein-cholesterol (LDL-C) (44 ± 9 vs 73 ± 6, p < 0.001) and high density lipoprotein cholesterol (HDL-C) (39 ± 2 vs 61 ± 5, p < 0.001), were significantly lowered in patients versus normal peers. Carotid arteries intima media thickness (CAIMT) of both side were significantly increased for patients (Rt 0.62 ± 0.2 vs. 0.29 ± 0.07 mm, p = 0.001 & Lt 0.66 ± 0.17 vs 0.29 ± 0.05 mm, p = 0.001) when compared with healthy controls, and showed positive correlation with, serum triglyceride, atherogenic index of plasma, and serum Osteoprotegerin levels. ELISA assay of serum Osteoprotegerin (OPG) revealed significantly higher levels for thalassemia patients than matched healthy controls (427 ± 102 vs. 324 ± 126 pg/ml, p = 0.02). Of particular interest is the obvious positive correlation between OPG levels and CAIMT of both sides (Rt r 0.54, p = 0.001 &Lt r 0.479, p = 0.001) and also with serum triglycerides (r 0.374, p = 0.03).ConclusionsSubclinical atherosclerosis started prematurely in children with beta- thalassemia. Carotid artery intima media thickness represented a simple, accurate and non-invasivemodality for early detection ofatherosclerosis. It was correlated well with serum Osteoprotegerin; this finding highlighte...

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“…Unlike free iron, solid indications point to excellular hemoglobin involvement in LDL oxidation and atherosclerosis ( , ). A positive correlation was demonstrated between elevated levels of oxidized LDL and intravascular rupture of erythrocytes in uremic patients undergoing hemodialysis who are prone to atherosclerosis ( − ).…”

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confidence: 99%

Mechanism of Low-Density Lipoprotein Oxidation by Hemoglobin-Derived Iron

et al. 2003

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Excellular hemoglobin is an extremely active oxidant of low-density lipoproteins (LDL), a phenomenon explained so far by different mechanisms. In this study, we analyzed the mechanism of met-hemoglobin oxidability by comparing its mode of operation with other hemoproteins, met-myoglobin and horseradish peroxidase (HRP) or with free hemin. The kinetics of met-hemoglobin activity toward LDL lipids and protein differed from that of met-myoglobin and HRP, both quantitatively and qualitatively. Those differences were further clarified by analyzing heme transfer from the above-mentioned hemoproteins to LDL. It appeared that met-hemoglobin transferred most of its hemin to LDL, and the presence of H(2)O(2) accelerated the process. In contrast, met-myoglobin partially released hemin, but only in the presence of H(2)O(2), while HRP could not transfer heme at all. The minor amount of hemin transferred from met-myoglobin to LDL sufficed to trigger ApoB oxidation, forming covalent aggregates via inter-bityrosines. This indicated that heme bound to high affinity site(s) is responsible for oxidation. LDL components providing the sites were analyzed by binding heme-CO monomers to LDL. Soret spectra revealed that the high affinity site of monomeric hemin is located on the LDL protein, ApoB. The complex heme-CO-ApoB underwent instantaneous oxidation to hemin-ApoB, and the bound hemin then slowly disintegrated in conjunction with LDL oxidation. Hemopexin prevented LDL oxidation by trapping hemoprotein transferable heme. We concluded that met-hemoglobin exerts its oxidative activity on LDL via transfer of heme, which serves as a vehicle for iron insertion into the LDL protein, leading to formation of atherogenic LDL aggregates.

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The interaction between ruptured erythrocytes and low‐density lipoproteins

Cited by 65 publications

References 36 publications

Atherogenesis May Involve the Prooxidant and Proinflammatory Effects of Ferryl Hemoglobin

Atherogenesis May Involve the Prooxidant and Proinflammatory Effects of Ferryl Hemoglobin

Premature atherosclerosis in children with beta-thalassemia major: New diagnostic marker

Mechanism of Low-Density Lipoprotein Oxidation by Hemoglobin-Derived Iron

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