The Oxidized Lipoproteins In Vivo: Its Diversity and Behavior in the Human Circulation.

A high concentration of low-density lipoproteins (LDLs) in circulation has been well-known as a major risk factor for cardiovascular diseases. The presence of oxidized LDLs (oxLDLs) in atherosclerotic lesions and circulation was demonstrated using anti-oxLDL monoclonal antibodies. The so-called "oxLDL hypothesis", as a mechanism for atherosclerosis development, has been attracting attention for decades. However, the oxLDL has been considered a hypothetical particle since the oxLDL present in vivo has not been fully characterized. Several chemically modified LDLs have been proposed to mimic oxLDLs. Some of the subfractions of LDL, especially Lp(a) and electronegative LDL, have been characterized as oxLDL candidates as oxidized phospholipids that stimulate vascular cells. Oxidized high-density lipoprotein (oxHDL) and oxLDL were discovered immunologically in vivo. Recently, an oxLDL-oxHDL complex was found in human plasma, suggesting the involvement of HDLs in the oxidative modification of lipoproteins in vivo. In this review, we summarize our understanding of oxidized lipoproteins and propose a novel standpoint to understand the oxidized lipoproteins present in vivo.

Effects of a lifestyle intervention on markers of cardiometabolic risk and oxidized lipoproteins among obese adolescents with prediabetes.

OBJECTIVE: Obesity and hyperglycaemia contribute to the atherosclerotic process in part through oxidative modifications to lipoprotein particles. The present study aimed to evaluate the effects of a lifestyle intervention on markers of oxidized lipoproteins in obese Latino adolescents with prediabetes. DESIGN: Pre-post design. SETTING: Participants were enrolled into a 12-week lifestyle intervention. Measurements pre- and post-intervention included anthropometrics and body composition, lipid panel, oxidized LDL (oxLDL), oxidized HDL (oxHDL), intake of fresh fruits and vegetables, and cardiorespiratory fitness. PARTICIPANTS: Thirty-five obese Latino adolescents (seventeen females, eighteen males; mean age 15·5 (sd 1·0) years; mean BMI percentile 98·5 (sd 1·2)) with prediabetes. RESULTS: Intervention participation resulted in significant reductions in weight (-1·2 %, P = 0·042), BMI and BMI percentile (-2·0 and -0·4 %, respectively, P < 0·001), body fat (-7·0 %, P = 0·025), TAG (-11·8 %, P = 0·032), total cholesterol (-5·0 %, P = 0·002), VLDL-cholesterol (-12·5 %, P = 0·029), and non-HDL-cholesterol (-6·7 %, P = 0·007). Additionally, fitness (6·4 %, P < 0·001) and intake of fruits and vegetables (42·4 %, P = 0·025) increased significantly. OxLDL decreased significantly after the intervention (51·0 (sd 14·0) v. 48·7 (sd 12·8) U/l, P = 0·022), while oxHDL trended towards a significant increase (395·2 (sd 94·6) v. 416·1 (sd 98·4) ng/ml, P = 0·056). CONCLUSIONS: These data support the utility of lifestyle intervention to improve the atherogenic phenotype of Latino adolescents who are at high risk for developing premature CVD and type 2 diabetes.

Relationships of oxidized HDL with blood coagulation and fibrinolysis in patients with type 2 diabetes mellitus.

Although oxidization of LDL is known to be a crucial step for atherosclerotic progression, the significance of oxidized HDL remains to be clarified. The purpose of this study was to determine the relationships of oxidized HDL with blood coagulation and fibrinolysis in patients with diabetes. The subjects were outpatients with type 2 diabetes (n = 163; median hemoglobin A1c, 6.9%). Activities of blood coagulation and fibrinolysis were evaluated by levels of thrombin-anti-thrombin complex (TAT) and plasmin-α2 plasmin inhibitor complex (PIC), respectively. Relationships of oxidized HDL with TAT and PIC were investigated by using linear regression analysis and logistic regression analysis. Oxidized HDL showed a significant inverse correlation with TAT and a marginally significant correlation with PIC (Spearman's rank correlation coefficient: TAT, - 0.205 [p < 0.01]; PIC, - 0.135 [p = 0.087]). Prevalence of high TAT was significantly lower in the 3rd tertile group for oxidized HDL than in its 1st tertile (20.4 vs. 5.6%, p < 0.05), and prevalence of high PIC was marginally significantly lower in the 3rd tertile group for oxidized HDL than in its 1st tertile (40.7 vs. 24.1%, p = 0.099). In multivariate logistic regression analysis using age, gender, smoking, alcohol drinking, BMI, hemoglobin A1c, therapy for dyslipidemia, therapy for diabetes and anti-coagulation therapy as explanatory variables, odds ratios for high TAT and high PIC in the 3rd tertile group for oxidized HDL versus its 1st tertile group were significantly lower than the reference level of 1.00 (high TAT: 0.19 [0.04-0.99], p < 0.05; high PIC: 0.33 [0.12-0.95], p < 0.05). The frequency of high TAT or high PIC was lower in the higher tertile group for oxidized HDL than in its lower tertile group. Thus, oxidized HDL is thought to be inversely associated with both blood coagulation and fibrinolysis in patients with type 2 diabetes.

Oxidation-induced loss of the ability of HDL to counteract the inhibitory effect of oxidized LDL on vasorelaxation.

Several current diseases are associated with an increase in the oxidation of HDL, which is likely to impair their functionality. Our aim was to identify whether oxidation could change the protective effect of HDL against the deleterious effect on vasoreactivity induced by oxidative stress. HDL from healthy subjects were oxidized in vitro by Cu(2+), and the ability of oxidized HDL to counteract the inhibitory effect of oxidized LDL on acetylcholine-induced vasodilation was tested on isolated rabbit aorta rings. Oxidation of HDL was evidenced by the increase in the 7-oxysterols/cholesterol ratio (3.20 ± 1.12 vs 0.02 ± 0.01 % in native HDL, p < 0.05). Oxidized LDL inhibited endothelium-dependent vasodilation (E max = 50.2 ± 5.0 vs 92.5 ± 1.7 % for incubation in Kreb's buffer, p < 0.05) and native HDL counteracted this inhibition (E max = 72.4 ± 4.8 vs 50.2 ± 5.0 % p < 0.05). At the opposite, oxidized HDL had no effect on oxidized LDL-induced inhibition on endothelium-dependent vasorelaxation (E max = 53.7 ± 4.8 vs 50.2 ± 5.0 %, NS). HDL oxidation is associated with a decreased ability of HDL to remove 7-oxysterols from oxidized LDL. In conclusion, these results show that oxidation of HDL induces the loss of their protective effect against endothelial dysfunction, which could promote atherosclerosis in diseases associated with increased oxidative stress.

Oxidized HDL induces cytotoxic effects: implications for atherogenic mechanism.

Atherosclerosis can be considered as an inflammatory disease and oxidized low-density lipoprotein (oxLDL) is a critical factor in atherogenesis. Although high-density lipoprotein (HDL) is generally an antiatherogenic lipoprotein, this property can be compromised by functional impairment mainly due to oxidative modification. As such, understanding the proatherogenic properties exerted by oxidized-HDL (oxHDL) becomes more important. This study was focused on examining the role of oxHDL as a proatherogenic agent, using oxLDL as a positive control. The comparative toxicity of oxHDL and oxLDL having same range of malondialdehyde, to monocytes was evaluated. After treatment, markers for oxidative stress, inflammation, and cytotoxicity were quantitated. The results showed that like oxLDL, oxHDL induced significant oxidative stress, cytotoxicity, and release of TNF -alpha and MMP-9 in monocytes/macrophages, but was less potent than oxLDL in promoting these proatherogenic effects. Further, the effects of oxHDL for the enhanced formation of MMP-9 were found to be mediated by NADPH oxidase/ROS-JNK/ERK pathway, as one mechanism.

Sepsis-Induced Coagulopathy Phenotype Induced by Oxidized High-Density Lipoprotein Associated with Increased Mortality in Septic-Shock Patients.

Sepsis syndrome is a highly lethal uncontrolled response to an infection, which is characterized by sepsis-induced coagulopathy (SIC). High-density lipoprotein (HDL) exhibits antithrombotic activity, regulating coagulation in vascular endothelial cells. Sepsis induces the release of several proinflammatory molecules, including reactive oxygen species, which lead to an increase in oxidative stress in blood vessels. Thus, circulating lipoproteins, such as HDL, are oxidized to oxHDL, which promotes hemostatic dysfunction, acquiring prothrombotic properties linked to the severity of organ failure in septic-shock patients (SSP). However, a rigorous and comprehensive investigation demonstrating that oxHDL is associated with a coagulopathy-associated deleterious outcome of SSP, has not been reported. Thus, we investigated the participation of plasma oxHDL in coagulopathy-associated sepsis pathogenesis and elucidated the underlying molecular mechanism. A prospective study was conducted on 42 patients admitted to intensive care units, (26 SSP and 16 non-SSP) and 39 healthy volunteers. We found that an increased plasma oxHDL level in SSP was associated with a prothrombotic phenotype, increased mortality and elevated risk of death, which predicts mortality in SSP. The underlying mechanism indicates that oxHDL triggers an endothelial protein expression reprogramming of coagulation factors and procoagulant adhesion proteins, to produce a prothrombotic environment, mainly mediated by the endothelial LOX-1 receptor. Our study demonstrates that an increased plasma oxHDL level is associated with coagulopathy in SSP through a mechanism involving the endothelial LOX-1 receptor and endothelial protein expression regulation. Therefore, the plasma oxHDL level plays a role in the molecular mechanism associated with increased mortality in SSP.

Oxidized High-Density Lipoprotein Shows a Stepwise Increase as Fibrosis Progresses in Patients with Nonalcoholic Fatty Liver Disease.

Patients with nonalcoholic fatty liver disease (NAFLD) show dyslipidemia and a high risk for coronary heart disease (CHD). However, conventional atherosclerotic lipids are found at low levels in NAFLD patients with advanced fibrosis, in whom the risk for CHD is extremely high. The aim of the present study was to evaluate the levels of oxidized high-density lipoprotein (oxHDL), an emerging atherosclerotic biomarker, in patients with NAFLD. A total of 32 non-NAFLD subjects and 106 patients with NAFLD were enrolled. The fibrosis grades were stratified using non-invasive methods, including the Fibrosis-4 index and NAFLD fibrosis score. Total cholesterol and low-density lipoprotein (LDL)-cholesterol levels were significantly low in patients with advanced liver fibrosis. In contrast, oxHDL levels were high in NAFLD patients and showed a stepwise increase as fibrosis progressed. These oxHDL levels were independent of the HDL cholesterol levels, and statin use did not influence the oxHDL levels. Obese patients showed no increase in oxHDL levels, whereas patients with a low handgrip strength showed high oxHDL levels in NAFLD with advanced fibrosis. In conclusion, oxHDL is a potential biomarker for assessing the status of patients with NAFLD, including CHD and metabolic/nutritional disturbance, and particular cases with advanced liver fibrosis.

Structure and Dynamics of Oxidized Lipoproteins In Vivo: Roles of High-Density Lipoprotein.

Oxidative modification of lipoproteins is implicated in the occurrence and development of atherosclerotic lesions. Earlier studies have elucidated on the mechanisms of foam cell formation and lipid accumulation in these lesions, which is mediated by scavenger receptor-mediated endocytosis of oxidized low-density lipoprotein (oxLDL). Mounting clinical evidence has supported the involvement of oxLDL in cardiovascular diseases. High-density lipoprotein (HDL) is known as anti-atherogenic; however, recent studies have shown circulating oxidized HDL (oxHDL) is related to cardiovascular diseases. A modified structure of oxLDL, which was increased in the plasma of patients with acute myocardial infarction, was characterized. It had two unique features: (1) a fraction of oxLDL accompanied oxHDL, and (2) apoA1 was heavily modified, while modification of apoB, and the accumulation of oxidized phosphatidylcholine (oxPC) and lysophosphatidylcholine (lysoPC) was less pronounced. When LDL and HDL were present at the same time, oxidized lipoproteins actively interacted with each other, and oxPC and lysoPC were transferred to another lipoprotein particle and enzymatically metabolized rapidly. This brief review provides a novel view on the dynamics of oxLDL and oxHDL in circulation.

OX-HDL: A Starring Role in Cardiorenal Syndrome and the Effects of Heme Oxygenase-1 Intervention.

In this review, we will evaluate how high-density lipoprotein (HDL) and the reverse cholesterol transport (RCT) pathway are critical for proper cardiovascular-renal physiology. We will begin by reviewing the basic concepts of HDL cholesterol synthesis and pathway regulation, followed by cardiorenal syndrome (CRS) pathophysiology. After explaining how the HDL and RCT pathways become dysfunctional through oxidative processes, we will elaborate on the potential role of HDL dysfunction in CRS. We will then present findings on how HDL function and the inducible antioxidant gene heme oxygenase-1 (HO-1) are interconnected and how induction of HO-1 is protective against HDL dysfunction and important for the proper functioning of the cardiovascular-renal system. This will substantiate the proposal of HO-1 as a novel therapeutic target to prevent HDL dysfunction and, consequently, cardiovascular disease, renal dysfunction, and the onset of CRS.

The Effects of Heme Oxygenase Upregulation on Obesity and the Metabolic Syndrome.

Significance: Obesity is a chronic condition that is characterized by inflammation and oxidative stress with consequent cardiovascular complications of hypertension, dyslipidemia, and vascular dysfunction. Obesity-induced metabolic syndrome remains an epidemic of global proportions. Recent Advances: Gene targeting of the endothelium with a retrovirus using an endothelium-specific promoter vascular endothelium cadherin (VECAD)-HO-1 offers a potential long-term solution to adiposity by targeting the endothelium. This has resulted in improvements of both vascular function and adiposity attenuation. Critical Issues: Heme oxygenase plays an ever-increasing role in the understanding of human biology in the complex conditions of obesity and the metabolic syndrome. The heme oxygenase 1 (HO-1) system creates biliverdin/bilirubin, which functions as an antioxidant, and carbon monoxide, which has antiapoptotic properties. Future Directions: Upregulation of HO-1 has been shown to improve adiposity as well as vascular function in both animal and human studies.

Increased Oxidized High-Density Lipoprotein/High-Density Lipoprotein-Cholesterol Ratio as a Potential Indicator of Disturbed Metabolic Health in Overweight and Obese Individuals.

BACKGROUND: We evaluated the qualitative characteristics of high-density lipoprotein (HDL) particles in metabolically healthy and unhealthy overweight and obese subjects. METHODS: The study involved 115 subject individuals classified as metabolically healthy and unhealthy, as in overweight and obese groups. Commercial enzyme-linked immunosorbent assay (ELISA) kits were used to measure oxidized HDL (OxHDL) and serum amyloid A (SAA) concentrations. Lipoprotein subfractions were separated using nondenaturing gradient gel electrophoresis. RESULTS: An independent association was shown between increased OxHDL/HDL-cholesterol ratio and the occurrence of metabolically unhealthy phenotype in the overweight and obese groups. The OxHDL/HDL-cholesterol ratio showed excellent and acceptable diagnostic accuracy in determination of metabolic health phenotypes (overweight group, AUC = 0.881; obese group, AUC = 0.765). Accumulation of smaller HDL particles in metabolically unhealthy subjects was verified by lipoprotein subfraction analysis. SAA concentrations did not differ significantly between phenotypes. CONCLUSIONS: Increased OxHDL/HDL-cholesterol ratio may be a potential indicator of disturbed metabolic health in overweight and obese individuals.

Oxidized HDL, as a Novel Biomarker for Calcific Aortic Valve Disease, Promotes the Calcification of Aortic Valve Interstitial Cells.

Calcific aortic valve disease (CAVD) is characterized by progressive mineralization of the aortic valve. Lipid infiltration and oxidative stress are the driving forces for the initiation and development of this disease. However, it remains unknown whether oxidized high-density lipoprotein (ox-HDL) plays a role in the mineralization of aortic valve interstitial cells (AVICs). Serum ox-HDL levels were determined in 168 severe CAVD patients and 168 age- and gender-matched non-CAVD controls. Results showed that ox-HDL concentrations were significantly increased in CAVD compared with the control group (131.52 ± 30.96 ng/mL vs. 112.58 ± 32.20 ng/mL, P < 0.001) and were correlated with CAVD severity. Multivariable logistic regression revealed that ox-HDL levels were independently associated with CAVD after adjusting for the incidence of coronary artery disease (CAD) (odds ratio 1.019, 95% CI 1.012-1.027, P < 0.001) or atherosclerotic risk factors (odds ratio 1.027, 95% CI 1.017-1.037, P < 0.001). Chronic ox-HDL stimulation of AVICs increased alkaline phosphatase activity (ALP) and calcium deposits in AVICs in vitro. Mechanistic studies further showed that ox-HDL upregulated several osteogenic factors, including BMP-2, Runx2, and Msx2 expressions in AVICs. This is the first study to demonstrate a relationship between increased ox-HDL concentration and CAVD incidence.

Effects of a Two-Year Home-Based Exercise Training Program on Oxidized LDL and HDL Lipids in Coronary Artery Disease Patients with and without Type-2 Diabetes.

We investigated the effect of two-year home-based exercise training program on oxidized low-density lipoprotein LDL (ox-LDL) and high-density lipoprotein HDL (ox-HDL) lipids in patients with coronary artery disease (CAD), both with and without type-2 diabetes (T2D). Analysis of lipoprotein-oxidized lipids was based on the determination of baseline conjugated dienes in lipoprotein lipids. In order to study the effect of an exercise load on ox-LDL and ox-HDL lipids patients in both CAD and CAD + T2D intervention, groups were divided in three based on exercise load (high, medium, and low). During the two-year home-based exercise training program, the study showed that only higher training volume resulted in a decreased concentration of ox-LDL, while the two groups with lower training volumes showed no change. This result indicates that the training load needs to be sufficiently high in order to decrease the concentration of atherogenic ox-LDL lipids in patients with CAD and CAD + T2D. Interestingly, the concentration of ox-HDL did not change in any of the subgroups. This could indicate that the lipid peroxide-transporting capacity of HDL, suggested by results from exercise training studies in healthy adults, may not function similarly in CAD patients with or without T2D. Moreover, the lipid-lowering medication used may have had an influence on these results.

Apolipoprotein A-1 mimetic peptide 4F promotes endothelial repairing and compromises reendothelialization impaired by oxidized HDL through SR-B1.

Disruption of endothelial monolayer integrity is the primary instigating factor for many cardiovascular diseases. High density lipoprotein (HDL) oxidized by heme enzyme myeloperoxidase (MPO) is dysfunctional in promoting endothelial repair. Apolipoprotein A-1 mimetic 4F with its pleiotropic benefits has been proven effective in many in vivo models. In this study we investigated whether 4F promotes endothelial repair and restores the impaired function of oxidized HDL (Cl/NO2-HDL) in promoting re-endothelialization. We demonstrate that 4F and Cl/NO2-HDL act on scavenger receptor type I (SR-B1) using human aorta endothelial cells (HAEC) and SR-B1 (-/-) mouse aortic endothelial cells. Wound healing, transwell migration, lamellipodia formation and single cell migration assay experiments show that 4F treatment is associated with a recovery of endothelial cell migration and associated with significantly increased endothelial nitric oxide synthase (eNOS) activity, Akt phosphorylation and SR-B1 expression. 4F increases NO generation and diminishes oxidative stress. In vivo, 4F can stimulate cell proliferation and re-endothelialization in the carotid artery after treatment with Cl/NO2-HDL in a carotid artery electric injury model but fails to do so in SR-B1(-/-) mice. These findings demonstrate that 4F promotes endothelial cell migration and has a potential therapeutic benefit against early endothelial injury in cardiovascular diseases.

Mildly oxidized HDL decrease agonist-induced platelet aggregation and release of pro-coagulant platelet extracellular vesicles.

Stored platelet concentrates (PLCs) for therapeutic purpose, develop a platelet storage lesion (PSL), characterized by impaired platelet (PLT) viability and function, platelet extracellular vesicle (PL-EV) release and profound lipidomic changes. Whereas oxidized low-density lipoprotein (oxLDL) activates PLTs and promotes atherosclerosis, effects linked to oxidized high-density lipoprotein (oxHDL) are poorly characterized. PLCs from blood donors were treated with native (nHDL) or mildly oxidized HDL (moxHDL) for 5days under blood banking conditions. Flow cytometry, nanoparticle tracking analysis (NTA), aggregometry, immunoblot analysis and mass spectrometry were carried out to analyze PL-EV and platelet exosomes (PL-EX) release, PLT aggregation, protein expression, and PLT and plasma lipid composition. In comparison to total nHDL, moxHDL significantly decreased PL-EV release by -36% after 5days of PLT storage and partially reversed agonist-induced PLT aggregation. PL-EV release positively correlated with PLT aggregation. MoxHDL improved PLT membrane lipid homeostasis through enhanced uptake of lysophospholipids and their remodeling to corresponding phospholipid species. This also appeared for sphingomyelin (SM) and d18:0/d18:1 sphingosine-1-phosphate (S1P) at the expense of ceramide (Cer) and hexosylceramide (HexCer) leading to reduced Cer/S1P ratio as PLT-viability indicator. This membrane remodeling was associated with increased content of CD36 and maturation of scavenger receptor-B1 (SR-B1) protein in secreted PL-EVs. MoxHDL, more potently than nHDL, improves PLT-membrane lipid homeostasis, partially antagonizes PL-EV release and agonist-induced PLT aggregation. Altogether, this may be the result of more efficient phospho- and sphingolipid remodeling mediated by CD36 and SR-B1 in the absence of ABCA1 on PLTs. As in vitro supplement in PLCs, moxHDL has the potential to improve PLC quality and to prolong storage.

6-mo aerobic exercise intervention enhances the lipid peroxide transport function of HDL.

During acute exercise, the concentration of oxidized high-density lipoprotein (HDL) lipids (ox-HDL) is reported to increase suggesting that HDL may function in decreasing the concentration of oxidized low-density lipoprotein (LDL) lipids. However, the effect of exercise intervention on the lipid peroxide transport function of HDL is unknown. A randomized controlled trial with sedentary women (N = 161), aged 43-63, with no current use of hormone therapy, were randomized into a 6-month (mo) exercise group and a control group. During the 6-mo intervention, the concentration of ox-HDL increased in the exercise group by 5% and decreased in the control group by 2% (p = .003). Also, the ratio of ox-HDL to HDL-cholesterol increased by 5% in the exercise group and decreased by 1.5% in the control group (p = .036). The concentrations of cholesteryl ester transfer protein (CETP) and adiponectin did not change during the intervention. The concentration of serum triglycerides trended to decrease by 6% in the intervention group (p = .051). We found that the concentration of ox-HDL increased during the 6-mo aerobic exercise intervention, but the increase was not related to changes in the levels of CETP or adiponectin. These results, together with earlier studies, suggest that HDL has an active role in the reverse transport of lipid peroxides.

Elevated CETP activity during acute phase of myocardial infarction is independently associated with endothelial dysfunction and adverse clinical outcome.

OBJECTIVE: Recent data suggests that cholesteryl ester transfer protein (CETP) activity may interact with acute stress conditions via inflammatory-oxidative response and thrombogenesis. We investigated this assumption in patients with ST-elevation myocardial infarction (STEMI). METHODS: Consecutive patients with STEMI (n = 116) were enrolled <24-h of symptoms onset and were followed for 180 days. Plasma levels of C-reactive protein (CRP), interleukin-2 (IL-2), tumor necrosis factor (TNFα), 8-isoprostane, nitric oxide (NOx) and CETP activity were measured at enrollment (D1) and at fifth day (D5). Flow-mediated dilation (FMD) was assessed by ultrasound and coronary thrombus burden (CTB) was evaluated by angiography. RESULTS: Neither baseline nor the change of CETP activity from D1 to D5 was associated with CRP, IL-2, TNFα, 8-isoprostane levels or CTB. The rise in NOx from D1 to D5 was inferior [3.5(-1; 10) vs. 5.5(-1; 12); p < 0.001] and FMD was lower [5.9(5.5) vs. 9.6(6.6); p = 0.047] in patients with baseline CETP activity above the median value than in their counterparts. Oxidized HDL was measured by thiobarbituric acid reactive substances (TBARS) in isolated HDL particles and increased from D1 to D5, and remaining elevated at D30. The change in TBARS content in HDL was associated with CETP activity (r = 0.72; p = 0.014) and FMD (r = -0.61; p = 0.046). High CETP activity at admission was associated with the incidence of sudden death and recurrent MI at 30 days (OR 12.8; 95% CI 1.25-132; p = 0.032) and 180 days (OR 3.3; 95% CI 1.03-10.7; p = 0.044). CONCLUSIONS: An enhanced CETP activity during acute phase of STEMI is independently associated with endothelial dysfunction and adverse clinical outcome.

Cupremia y colesterolemia como factores de riesgo en pacientes con enfermedad de Alzheimer / Plasma levels of copper and cholesterol as risk factors in Alzheimer disease patients / Cupremia e colesterolemia como fatores de risco em pacientes com doença de Alzheimer

Se estudiaron 241 personas, 119 controles y 122 pacientes con enfermedad de Alzheimer (EA) subagrupados en tres categorías de acuerdo con el estadio clínico de la dolencia, con el objetivo de investigar la influencia de niveles elevados de cobre libre y colesterol plasmático como factores de riesgo para la EA. Las conclusiones obtenidas de los resultados indicaron que los pacientes expuestos a una combinación de alto colesterol y de cobre no unido a ceruloplasmina tuvieron mayor proporción de marcadores de estrés oxidativo (carbonilos proteicos, sustancias reactivas al tiobarbiturato, glutatión oxidado y descenso de antioxidantes totales en sangre), conjuntamente con un incremento de HDL-colesterol peroxidado y lipoproteína "a" que correlacionó con la gravedad de su cuadro. Lo mismo sucedió con la relación entre péptidos amiloides (1-40) y (1-42) en plasma y los valores del mini-test de estado cognitivo (MMSE). Se halló que una función de adición de efectos que cuantificó el daño por cobre libre y colesterol oxidado resultó directamente proporcional a la pérdida de desempeño cognitivo estimada por medio del MMSE. Esta función es de fácil determinación y puede considerarse un nuevo biomarcador para estudiar riesgo en poblaciones expuestas, apoyar el diagnóstico clínico, o evaluar la eficacia de estrategias terapéuticas en pacientes con EA.

Alzheimer disease (AD) patients (122) compared to control subjects (119) were studied to determine the role of chronic exposure of hypercholesterolemic plasma levels and free copper (not bound to ceruloplasmin) as biomarkers of progression for AD. Oxidative stress parameters, lipid profile, amyloid levels, and cognitive status were studied in all participants. Conclusions obtained indicated that patients exposed simultaneously to free copper and increased cholesterol levels present higher indicators of oxidative stress (protein carbonyls, thiobarbituric acid-reactive substances, decreased total antioxidant activity in plasma and elevated oxidized HDL-cholesterol). Lipoprotein "a" concentrations also correlated with the clinical progression of the disease. The ratio amyloid ß(1-40)/ß(1-42) in plasma inversely correlated with the cognitive performance estimated by the Mini-Mental State Examination Test (MMSE). A defined function that weighs the contribution of the deleterious effect produced by combined free copper and Ox-HDL-cholesterol exposure directly correlated with the loss of cognitive performance. Thus, this biomarker could be a new tool for the screening of large populations under risk, or may be a useful way to estimate the efficacy of therapeuti approaches in patients suffering AD.

Foram estudadas 241 pessoas, 119 controles e 122 pacientes com doença de Alzheimer (DA), agrupados em três categorias de acordo com o estágio clínico da doença, com o objetivo de investigar a influência de níveis elevados de cobre livre e colesterol plasmático como fatores de risco para a DA. As conclusões obtidas a partir dos resultados indicaram que os pacientes expostos a uma combinação de colesterol alto e de cobre não ligados à ceruloplasmina apresentaram maior proporção de marcadores de estresse oxidativo (carbonilos proteicos, substâncias reativas ao tiobarbiturato, glutationa oxidada e diminuição dos antioxidantes totais no sangue ), juntamente com um aumento da HDL-colesterol peroxidado e lipoproteína "a" que correlacionou com a gravidade de sua condição. O mesmo aconteceu com a relação entre os peptídeos amilóides (1-40) e (1-42) em plasma e os valores do mini-teste do estado cognitivo (MMSE). Verificou-se que uma função de adição de efeitos que quantificou o dano por cobre livre e colesterol oxidado resultou diretamente proporcional à perda de desempenho cognitivo estimada através do MMSE. Esta função é fácil de determinar e pode ser considerada um novo biomarcador para estudar o risco em populações expostas, apoiar o diagnóstico clínico ou avaliar a eficácia de estratégias terapêuticas em pacientes com DA.