ubiquinone and Atherosclerosis

Topics: Animals; Atherosclerosis; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Muscular Diseases; Risk Factors; Ubiquinone

Atherosclerosis is the most common cause of cardiac deaths worldwide. Classically, atherosclerosis has been explained as a simple arterial lipid deposition with concomitant loss of vascular elasticity. Eventually, this condition can lead to consequent blood flow reduction through the affected vessel. However, numerous studies have demonstrated that more factors than lipid accumulation are involved in arterial damage at the cellular level, such as inflammation, autophagy impairment, mitochondrial dysfunction, and/or free-radical overproduction. In order to consider the correction of all of these pathological changes, new approaches in atherosclerosis treatment are necessary. Ubiquinone or coenzyme Q

Topics: Atherosclerosis; Dietary Supplements; Humans; Ubiquinone; Vitamins

A considerable body of data from genetic and epidemiological studies strongly support a causal relationship between high lipoprotein(a) [Lp(a)] levels, and the development of atherosclerosis and cardiovascular disease. This relationship is continuous, unrelated to Lp(a) threshold, and independent of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels. Unfortunately, the mechanism(s) through which Lp(a) promotes atherosclerosis are not clarified yet. Suggested hypotheses include: an increased Lp(a)-associated cholesterol entrapment in the arterial intima followed by inflammatory cell recruitment, abnormal upload of proinflammatory oxidized phospholipids, impaired fibrinolysis by inhibition of plasminogen activation, and enhanced coagulation, through inhibition of the tissue factor pathway inhibitor. This review is aimed at summarizing the available evidence on the topic.. There are two clinical forms, isolated hyperlipidemia(a) [HyperLp(a)] with acceptable LDL-C levels (< 70 mg/dL), and combined elevation of Lp(a) and LDL-C in plasma. To date, no drugs that selectively decrease Lp(a) are available. Some novel lipid-lowering drugs can lower Lp(a) levels, but to a limited extent, as their main effect is aimed at decreasing LDL-C levels. Significant Lp(a) lowering effects were obtained with nicotinic acid at high doses. However, adverse effects apart, nicotinic acid is no longer prescribed and available in Europe for clinical use, after European Agency of Medicines (EMA) ban. The only effective therapeutic option for now is Lipoprotein Apheresis (LA), albeit with some limitations. Lastly, it is to be acknowledged that the body of evidence confirming that reducing plasma isolated elevation of Lp(a) brings cardiovascular benefit is still insufficient. However, the growing bulk of clinical, genetic, mechanistic, and epidemiological available evidence strongly suggests that Lp(a) is likely to be the smoking gun.

Topics: Adult; Antibodies, Monoclonal, Humanized; Atherosclerosis; Blood Component Removal; Cholesterol, LDL; Humans; Hypolipidemic Agents; Lipoprotein(a); Middle Aged; Niacin; Oligonucleotides, Antisense; Risk Factors; Ubiquinone

Atherothrombosis is a recurrent complication in APS and SLE patients. Oxidative stress has been suggested as a key player underlying this process. Autoantibodies have been pointed to as the main contributors to abnormality in the oxidative status observed in APS and SLE patients, promoting the increased production of oxidant species and the reduction of antioxidant molecules. This imbalance causes vascular damage through the activation of immune cells, including monocytes, lymphocytes and neutrophils, causing the expression of pro-inflammatory and procoagulant molecules, the formation of neutrophil extracellular traps and the adhesion of these cells to the endothelium; the induction of cellular apoptosis and impaired cell clearance, which in turn enhances autoantibody neogeneration; and cytotoxicity of endothelial cells. This review describes the mechanisms underlying the role of oxidative stress in the pathogenesis of atherothrombosis associated with APS and SLE, focused on the effect of autoantibodies, the different cell types involved and the diverse effectors, including cytokines, procoagulant proteins and their main modulators, such as oxidant/antioxidant species and intracellular pathways in each pathology. We further discuss new therapies aimed at restoring the oxidative stress balance and subsequently to tackle atherothrombosis in APS and SLE.

Topics: Acetylcysteine; Anticoagulants; Antioxidants; Antiphospholipid Syndrome; Atherosclerosis; Autoantibodies; beta 2-Glycoprotein I; Coagulants; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lupus Erythematosus, Systemic; Mitochondrial Diseases; Oxidative Stress; Reactive Oxygen Species; Recurrence; Thrombosis; Ubiquinone

Coronary artery disease (CAD) constitutes the most common cause of morbidity and mortality in developed countries. Statins effectively reduce low-density lipoprotein cholesterol, an important risk factor for CAD and related acute coronary syndromes. They are an extensively studied group of drugs with versatile properties. Overall, they are safe and effective drugs but their myotoxic potential cannot be overlooked. In this review we focus on the pathogenesis of statins' myopathic side effects. Statins can interfere with protein modification at multiple levels. They can affect protein prenylation, an important post-translational modification of membrane bound proteins. They can also adversely affect selenoprotein synthesis, or can interfere with the biosynthesis of dolichols, which are involved in the process of protein glycosylation. Statin-induced myopathy may be also associated with mitochondrial dysfunction. Statins remain the spearhead of our armamentarium in treating atherosclerotic disease. Consistent with their versatile properties it is anticipated to see in the future their indications to expand. Better understanding of the molecular mechanisms involved in statin-induced myopathy may help identify patient groups susceptible to statins' side effects, thereby increasing their safety.

Topics: Atherosclerosis; Cholesterol; Female; Glycosylation; GTP Phosphohydrolases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Male; Membrane Proteins; Muscular Diseases; Protein Processing, Post-Translational; Randomized Controlled Trials as Topic; Risk Factors; Ubiquinone

For a number of years, coenzyme Q (CoQ10 in humans) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in plasma, and extensively investigated its antioxidant role. These two functions constitute the basis on which research supporting the clinical use of CoQ10 is founded. Also at the inner mitochondrial membrane level, coenzyme Q is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the transition pore. Furthermore, recent data reveal that CoQ10 affects expression of genes involved in human cell signalling, metabolism, and transport and some of the effects of exogenously administered CoQ10 may be due to this property. Coenzyme Q is the only lipid soluble antioxidant synthesized endogenously. In its reduced form, CoQH2, ubiquinol, inhibits protein and DNA oxidation but it is the effect on lipid peroxidation that has been most deeply studied. Ubiquinol inhibits the peroxidation of cell membrane lipids and also that of lipoprotein lipids present in the circulation. Dietary supplementation with CoQ10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoproteins to the initiation of lipid peroxidation. Moreover, CoQ10 has a direct anti-atherogenic effect, which has been demonstrated in apolipoprotein E-deficient mice fed with a high-fat diet. In this model, supplementation with CoQ10 at pharmacological doses was capable of decreasing the absolute concentration of lipid hydroperoxides in atherosclerotic lesions and of minimizing the size of atherosclerotic lesions in the whole aorta. Whether these protective effects are only due to the antioxidant properties of coenzyme Q remains to be established; recent data point out that CoQ10 could have a direct effect on endothelial function. In patients with stable moderate CHF, oral CoQ10 supplementation was shown to ameliorate cardiac contractility and endothelial dysfunction. Recent data from our laboratory showed a strong correlation between endothelium bound extra cellular SOD (ecSOD) and flow-dependent endothelial-mediated dilation, a functional parameter commonly used as a biomarker of vascular function. The study also highlighted that supplementation with CoQ10 that significantly affects endothelium-bound ecSOD activity. Furthermore, we showed a significant correlation between increase in endothelial bound ecSOD ac

Topics: Animals; Antioxidants; Atherosclerosis; Coenzymes; Endothelium, Vascular; Energy Metabolism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infertility, Male; Lipid Metabolism; Lipids; Male; Mice; Mitochondria; Superoxide Dismutase; Ubiquinone

Atherosclerosis is a major risk factor for cardiovascular disease (CVD) and is known to be an inflammatory process. Statin therapy decreases both cholesterol and inflammation and is used in primary and secondary prevention of CVD. However, a statin induced decrease of plasma concentrations of the antioxidant coenzyme Q10 (CoQ10), may prevent the patients from reaching their optimal anti-inflammatory potential. Here, we studied the anti-inflammatory effect of Simvastatin therapy and CoQ10 supplementation.. 35 patients in primary prevention with Simvastatin (40 mg/day) were randomized to receive oral CoQ10 supplementation (400 mg/d) or placebo for 8 weeks. 20 patients with hypercholesterolemia who received no cholesterol-lowering treatment was a control group. Plasma concentrations of lipids and inflammatory biomarkers (interleukin-6 (IL6); -8 (IL8); -10 (IL10), tumor necrosis factor-α (TNFα); high-sensitivity C reactive protein (hsCRP)) as well as glycated hemoglobin (HbA1c) were quantified before and after the intervention.. No significant change in inflammatory markers or lipids was observed after CoQ10 supplementation Patients in Simvastatin therapy had significantly (P < 0.05) lower baseline concentration of IL6 (0.31 ± 0.03 pg/ml), IL8 (1.6 ± 0.1 pg/ml) IL10 (0.16 ± 0.02 pg/ml) and borderline (P = 0.053) lower TNFα (0.88 ± 0.05 pg/ml), but not hsCRP (1.34 ± 0.19 mg/l) compared with the control group (0.62 ± 0.08, 2.6 ± 0.2, 0.25 ± 0.01, 1.07 ± 0.09, and 1.90 ± 0.35, respectively).. Simvastatin therapy has beneficial effects on inflammatory markers in plasma, but CoQ10 supplementation seems to have no additional potentiating effect in patients in primary prevention. In contrast, glucose homeostasis may improve with CoQ10 supplementation.

Topics: Adult; Aged; Atherosclerosis; Biomarkers; C-Reactive Protein; Cytokines; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Inflammation; Male; Middle Aged; Simvastatin; Ubiquinone

Atherosclerosis, a chronic disease of the arteries, results from pathological processes including the accumulation and aggregation of oxidized low-density lipoprotein (oxLDL) in the vessel walls, development of neointima, formation of a fibrous cap, and migration of immune cells to damaged vascular endothelium. Recent studies have shown that mitochondrial dysfunction is closely associated with the development and progression of atherosclerosis. Idebenone, a short-chain benzoquinone similar in structure to coenzyme Q10, can effectively clear oxygen free radicals as an electron carrier and antioxidant. In the present study, we aim to investigate weather idebenone protects against atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice.. apoE-/- mice receiving a high-fat diet (HFD) were treated with idebenone for 16 weeks. A total of 60 mice were randomized into the following four groups: (1) HFD, (2) HFD and low-dose idebenone (100 mg/kg/d), (3) HFD and medium-dose idebenone (200 mg/kg/d), and (4) HFD and high-dose (400 mg/kg/d). Proteomic analysis was performed between the HFD and idebenone-high-dose group. Plaque analysis was carried out by histological and immunohistochemical staining. Western blot, TUNEL staining, and MitoSOX assays were performed in human umbilical vein endothelial cells (HUVECs) to investigate the SIRT3-SOD2-mtROS pathway.. Histological and morphological analysis demonstrated that idebenone significantly reduced plaque burden and plaque size. Idebenone treatment effectively stabilized the atherosclerotic plaques. In mice treated with idebenone, 351 up-regulated and 379 down-regulated proteins were found to be significantly altered in proteomic analysis. In particular, the expression of SIRT3, SOD2, and NLRP3 was significantly regulated in the idebenone treatment groups compared with the HFD group both in vivo and in vitro. We further confirmed that idebenone protected against endothelial cell damage and inhibited the production of mitochondrial reactive oxygen species (mtROS) in cholesterol-treated HUVECs.. We demonstrated that idebenone acted as a mitochondrial protective agent by inhibiting the activation of NLPR3 via the SIRT3-SOD2-mtROS pathway. Idebenone may be a promising therapy for patients with atherosclerosis by improving mitochondrial dysfunction and inhibiting oxidative stress.

Topics: Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; Cell Survival; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Transgenic; Mitochondria; Oxidative Stress; Proteomics; Random Allocation; Reactive Oxygen Species; Sirtuin 3; Superoxide Dismutase; Ubiquinone; Voltage-Sensitive Dye Imaging

Coenzyme Q10 (CoQ10) exists in a wide variety of foods and has promising cardiovascular benefits. However, its effects on platelets and integrin αIIbβ3 signaling during atherosclerosis have not been previously explored. Here, apolipoprotein E-deficient (ApoE-/-) mice were fed a standard diet, high-fat diet (HFD) or CoQ10-supplemented HFD for 12 weeks. We found that CoQ10 supplementation in ApoE-/- mice significantly alleviated formation of HFD-induced atherosclerotic lesions, and attenuated platelet hyper-aggregation and granule secretion, including CD62P, CD63 and CD40 ligand (CD40L) expression and platelet factor-4, β-thromboglobulin and activation normal T cell expressed and secreted (CCL5) release. CoQ10 supplementation decreased soluble fibrinogen and JON/A binding to αIIbβ3 on activated platelets, indicating that αIIbβ3-mediated inside-out signaling was attenuated. Additionally, CoQ10 down-regulated platelet αIIbβ3 outside-in signaling including decreasing phosphorylation of the β3 intracellular tail, cellular and sarcoma tyrosine-protein kinase (c-Src), and myosin light chain (MLC), and consistently attenuating platelet spreading and clot retraction. Importantly, platelet-monocyte aggregation that was primarily mediated by αIIbβ3 and can be blocked using an αIIbβ3-specific antagonist tirofiban was also markedly diminished by CoQ10. Thus, CoQ10 supplementation attenuates platelet hyper-reactivity via down-regulating both αIIbβ3 inside-out and outside-in signaling, which may play important preventive roles in atherothrombosis.

Topics: Animals; Atherosclerosis; Clot Retraction; Male; Mice; Mice, Knockout, ApoE; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Signal Transduction; Ubiquinone

Coenzyme Q10 (CoQ10) deficiency has been associated with statin-induced myopathy, and supplementation with CoQ10 may reduce inflammation markers. The effects of statins on CoQ10 and its anti-inflammatory properties have not been investigated in HIV-positive patients.. The objectives of this study were to examine the effect of rosuvastatin on CoQ10 and CoQ10/LDL ratio over 24-week SATURN-HIV trial, explore the associations between CoQ10 levels and markers of vascular disease, inflammation, and immune activation, and assess whether changes in CoQ10 affected the anti-inflammatory effects of statin therapy or were associated with myalgia symptoms.. This was a secondary analysis of the SATURN-HIV trial, a 96-week randomized clinical trial of 10 mg daily rosuvastatin vs. placebo in HIV-infected patients on antiretroviral therapy. We assessed the statin treatment effect on CoQ10 levels and CoQ10/LDL ratios and whether changes in these markers were related to myalgias. Relationships between CoQ10, subclinical vascular disease, and biomarkers of inflammation and immune activation were explored using Spearman correlations and multivariable regression models.. Overall, 147 patients were included. Median age was 46 years; 78% were male and 68% African American. At baseline, CoQ10 levels and CoQ10/LDL ratio were modestly correlated with markers of HIV disease, immune activation, and carotid distensibility. After 24 weeks of statin therapy, CoQ10 levels decreased (p = 0.002 for between group difference) and CoQ10/LDL ratio increased (p = 0.036). In the statin treatment arm, we did not find evidence of a relationship between changes in CoQ10 or CoQ10/LDL ration and changes in markers of inflammation or immune activation. There was a borderline statistically significant association between changes in CoQ10 and myalgia symptoms [OR 4.0 per 0.1 mg/L decrease in CoQ10, p = 0.07].. Twenty-four weeks of 10 mg daily rosuvastatin decreases CoQ10 concentration and increases CoQ10/LDL ratio in HIV-infected patients on antiretroviral therapy.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Atherosclerosis; Biomarkers; CD4 Lymphocyte Count; Female; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Risk Factors; Rosuvastatin Calcium; Ubiquinone; Viral Load

Recent studies have shown the role of miRNAs in macrophage reverse cholesterol transport and atherogenesis. We hypothesized that coenzyme Q10 (CoQ10) may increase macrophage reverse cholesterol transport by regulating miRNA expression that contributes to the prevention of atherosclerosis.. CoQ10 treatment suppressed oxidized low-density lipoprotein-induced macrophage foam cell formation by ameliorating the binding of activator protein-1 to the putative promoter region of miR-378 primary transcript, thus decreasing the miR-378 level and enhancing the ATP-binding cassette transporter G1-mediated macrophage cholesterol efflux to high-density lipoprotein. Subsequently, the axis of activator protein-1/miR-378/ATP-binding cassette transporter G1 cholesterol efflux was confirmed in peritoneal macrophages isolated from CoQ10-treated apolipoprotein E-deficient mice. Finally, CoQ10 consumption promoted macrophage reverse cholesterol transport and inhibited the progression of atherosclerosis in apolipoprotein E-deficient mice.. This study identified activator protein-1/miR-378/ATP-binding cassette transporter G1 as a novel cascade for CoQ10 in facilitating macrophage cholesterol efflux in vitro and in vivo. Our data thus imply that both CoQ10 and miR-378 are promising candidates for atherosclerosis prevention and treatment.

Topics: 3' Untranslated Regions; Animals; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cholesterol; Foam Cells; HEK293 Cells; Humans; Lipoproteins; Lipoproteins, LDL; Macrophages; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Promoter Regions, Genetic; RNA, Small Interfering; Transcription Factor AP-1; Transfection; Ubiquinone

Topics: Animals; Atherosclerosis; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Cholesterol; Humans; Lipoproteins; Macrophages; Male; MicroRNAs; Transcription Factor AP-1; Ubiquinone

Accelerated atherosclerosis is the major cause of mortality in patients on chronic hemodialysis (HD). The aim of this study was to evaluate the relation between coenzyme Q10 (CoQ10) levels and coronary flow reserve (CFR) in HD patients as an indicator of atherosclerosis. Seventy-one chronic HD patients and 65 age- and sex-matched healthy individuals were included in the study. Plasma CoQ10 levels were performed by high-performance liquid chromatography measurements. CFR was assessed by transthoracic Doppler echocardiography. Serum CoQ10 levels (1.36 ± 0.43 vs. 2.53 ± 0.55, P < 0.001) and CFR values (1.73 ± 0.11 vs. 2.32 ± 0.28, P < 0.001) were significantly lower in HD patients compared with controls. There was a significant positive correlation between CFR and serum levels of CoQ10 (r = 0.669, P < 0.001). A linear regression analysis showed that serum levels of CoQ10 were still significantly and positively correlated with CFR (regression coefficient = 0.235, P < 0.001). Our data have demonstrated that HD patients exhibit decreased plasma CoQ10 levels and CFR values. The study also showed for the first time that serum CoQ10 levels independently predict CFR in HD patients.

Topics: Adult; Atherosclerosis; Blood Flow Velocity; Case-Control Studies; Coronary Circulation; Coronary Vessels; Female; Humans; Male; Middle Aged; Renal Dialysis; Ubiquinone; Ultrasonography

Topics: Atherosclerosis; Coronary Circulation; Female; Humans; Male; Renal Dialysis; Ubiquinone

A number of recent studies suggest that mitochondrial oxidative damage may be associated with atherosclerosis and the metabolic syndrome. However, much of the evidence linking mitochondrial oxidative damage and excess reactive oxygen species (ROS) with these pathologies is circumstantial. Consequently the importance of mitochondrial ROS in the etiology of these disorders is unclear. Furthermore, the potential of decreasing mitochondrial ROS as a therapy for these indications is not known. We assessed the impact of decreasing mitochondrial oxidative damage and ROS with the mitochondria-targeted antioxidant MitoQ in models of atherosclerosis and the metabolic syndrome (fat-fed ApoE(-/-) mice and ATM(+/-)/ApoE(-/-) mice, which are also haploinsufficient for the protein kinase, ataxia telangiectasia mutated (ATM). MitoQ administered orally for 14weeks prevented the increased adiposity, hypercholesterolemia, and hypertriglyceridemia associated with the metabolic syndrome. MitoQ also corrected hyperglycemia and hepatic steatosis, induced changes in multiple metabolically relevant lipid species, and decreased DNA oxidative damage (8-oxo-G) in multiple organs. Although MitoQ did not affect overall atherosclerotic plaque area in fat-fed ATM(+/+)/ApoE(-/-) and ATM(+/-)/ApoE(-/-) mice, MitoQ reduced the macrophage content and cell proliferation within plaques and 8-oxo-G. MitoQ also significantly reduced mtDNA oxidative damage in the liver. Our data suggest that MitoQ inhibits the development of multiple features of the metabolic syndrome in these mice by affecting redox signaling pathways that depend on mitochondrial ROS such as hydrogen peroxide. These findings strengthen the growing view that elevated mitochondrial ROS contributes to the etiology of the metabolic syndrome and suggest a potential therapeutic role for mitochondria-targeted antioxidants.

Topics: Adiposity; Animals; Antioxidants; Apolipoproteins E; Ataxia Telangiectasia Mutated Proteins; Atherosclerosis; Blood Glucose; Cell Cycle Proteins; Cells, Cultured; Diet, High-Fat; DNA-Binding Proteins; Energy Metabolism; Female; Lipid Metabolism; Lipids; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Organ Size; Organophosphorus Compounds; Oxidative Stress; Oxygen Consumption; Plaque, Atherosclerotic; Protein Carbonylation; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Tumor Suppressor Proteins; Ubiquinone

Topics: Animals; Antioxidants; Apolipoproteins E; Ataxia Telangiectasia Mutated Proteins; Atherosclerosis; Cell Cycle Proteins; DNA-Binding Proteins; Female; Male; Metabolic Syndrome; Mitochondria; Organophosphorus Compounds; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins; Ubiquinone

Increased production of reactive oxygen species (ROS) as a result of decreased activities of mitochondrial electron transport chain (ETC) complexes plays a role in the development of many inflammatory diseases, including atherosclerosis. Our previous studies established that paraoxonase 2 (PON2) possesses antiatherogenic properties and is associated with lower ROS levels. The aim of the present study was to determine the mechanism by which PON2 modulates ROS production. In this report, we demonstrate that PON2-def mice on the hyperlipidemic apolipoprotein E(-/-) background (PON2-def/apolipoprotein E(-/-)) develop exacerbated atherosclerotic lesions with enhanced mitochondrial oxidative stress. We show that PON2 protein is localized to the inner mitochondrial membrane, where it is found associated with respiratory complex III. Employing surface-plasmon-resonance, we demonstrate that PON2 binds with high affinity to coenzyme Q(10), an important component of the ETC. Enhanced mitochondrial oxidative stress in PON2-def mice was accompanied by significantly reduced ETC complex I + III activities, oxygen consumption, and adenosine triphosphate levels in PON2-def mice. In contrast, overexpression of PON2 effectively protected mitochondria from antimycin- or oligomycin-mediated mitochondrial dysfunction. Our results illustrate that the antiatherogenic effects of PON2 are, in part, mediated by the role of PON2 in mitochondrial function.

Topics: Animals; Apolipoproteins E; Aryldialkylphosphatase; Atherosclerosis; Diet, Atherogenic; Electron Transport; Female; Humans; Isoenzymes; Mice; Mice, Knockout; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Ubiquinone

Dietary coenzyme Q10 reduces spontaneous atherosclerosis in the apoE-deficient mouse model of experimental atherosclerosis. We have shown previously that exposure to sidestream cigarette smoke (SSCS) enhances atherosclerotic lesion formation in apoE-deficient mice. The aim of the present study was to determine if CoQ10 protected against SSCS-mediated atherosclerosis. Female apoE-deficient mice were fed a saturated fat-enriched diet (SFD) alone, or supplemented with 1% wt/wt coenzyme Q10 (SFD-Q10). Mice in each diet group were exposed to SSCS for 4hrs/day, 5days/week in a whole-body exposure chamber maintained at 35+/-4mg smoke particulates/m(3). Mice kept in filtered ambient air served as controls. Mice were euthanized after either 6 or 15weeks of SSCS exposure and following measurements were performed: i) lung 7-ethoxyresorufin-O-deethylase (EROD) activity; ii) plasma cholesterol and CoQ10 concentrations; iii) aortic intimal area covered by atherosclerotic lesions; and, iv) pathological characterization of lesions. Lung EROD activity increased in SSCS mice of both diet groups, confirming SSCS exposure. Plasma concentrations of CoQ10 in SFD-Q10-fed mice were increased markedly in comparison to SFD-fed mice. Plasma cholesterol concentrations and distributions of cholesterol in lipoprotein fractions were unaffected by SSCS exposure. Dietary supplementation with CoQ10 significantly reduced atherosclerotic lesions in control mice. As reported previously, exposure to SSCS increased the size of lesions in apoE-/- mice at both time points. However, dietary supplementation with CoQ10 had no effect on atherosclerotic lesions augmented by SSCS exposure. The results suggest a role of oxidative processes in smoke-augmented atherosclerosis that are different than those mitigated by CoQ10.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Cholesterol; Cytochrome P-450 CYP1A1; Diet; Disease Models, Animal; Female; Lung; Mice; Smoke; Ubiquinone

Cardiovascular alterations and periodontal disease have been associated, although cardiovascular disease treatments have not yet been tested against periodontal alterations. We investigated effects of squalene, hydroxytyrosol and coenzyme Q(10) on gingival tissues of rabbits fed on an atherosclerotic diet. Forty-eight rabbits were distributed in six groups. Control group was fed on standard chow for 80 days. The rest were fed with an atherogenic diet for 50 days. After that, a group was sacrificed and the rest were subjected for another extra 30 days on commercial chow alone or supplemented with coenzyme Q(10), squalene or hydroxytyrosol. Atherosclerotic rabbits had higher fibrosis and endothelial activation and lower cellularity in gingival mucosa than controls (P<0.05). Hydroxytyrosol reduced endothelial activation (P<0.05) and squalene additionally decreased fibrosis (P<0.05). Results suggest that gingival vascular changes after the atherosclerotic diet have been reversed by hydroxytyrosol and squalene, natural products from the minor fraction of virgin olive oil.

Topics: Animals; Antioxidants; Arteries; Atherosclerosis; Collagen; Diet, Atherogenic; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Fibrosis; Gingiva; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mouth Mucosa; Olive Oil; Periodontal Diseases; Phenylethyl Alcohol; Plant Oils; Rabbits; Squalene; Ubiquinone

The effects of the administration of water soluble coenzyme Q10 (25 mg/kg per day) over 30 days, after 50 days feeding on a high-fat diet (3% lard + 1.3% cholesterol), were investigated in the plasma and liver mitochondria of rabbits. Results showed that this atherogenic diet enhanced lipid levels both in plasma and liver mitochondria, reduced plasma and mitochondrial concentrations of retinol and coenzyme Q10, led to higher DNA damage in peripheral blood lymphocytes and reactive oxygen species concentration in liver mitochondria. The treatment of animals with coenzyme Q10 reduced (to the healthy group levels) lipid concentration in liver mitochondria with no effect on plasma lipids, increased mitochondrial levels of alpha-tocopherol, restored mitochondrial coenzyme Q10 and improved alpha-tocopherol levels in plasma. Moreover, coenzyme Q10 supplementation reduced mitochondrial reactive oxygen species levels and decreased DNA damage in peripheral blood lymphocytes. The findings suggest that antioxidant therapy with coenzyme Q10 may be used in the treatment of liver pathologies associated to the intake of high-fat, atherogenic, diets.

Topics: Animals; Atherosclerosis; Diet, Atherogenic; DNA Damage; Lymphocytes; Male; Mitochondria, Liver; Models, Animal; Oxidative Stress; Rabbits; Reactive Oxygen Species; Ubiquinone; Vitamin A

Although many compounds have already been tested in-vitro to determine their antioxidant profile, it is necessary to investigate the in-vivo effect of potential antioxidants. However, representative models of systemic oxidative stress have been poorly studied. Here, different potential systemic oxidative stress animal models have been investigated. These included a vitamin E-deficient rat, a diabetic rat and an atherosclerotic rabbit model. Plasma/serum malondialdehyde was measured as a parameter of oxidative damage. Plasma/serum fat-soluble antioxidants were determined as markers of antioxidant defence. We demonstrated that vitamin E-deficient rats were not suitable as a model of systemic oxidative stress, whereas diabetic and atherosclerotic animals showed increased systemic oxidative damage, as reflected by significantly augmented plasma/serum malondialdehyde. Moreover, plasma coenzyme Q9 increased by 80% in diabetic rats, confirming systemic oxidative stress. In view of these observations and economically favouring factors, the diabetic rat appeared to be the most appropriate systemic oxidative stress model. These findings have provided important information concerning systemic oxidative stress animal models for the in-vivo study of antioxidants.

Topics: alpha-Tocopherol; Animals; Antioxidants; Atherosclerosis; Carbon Tetrachloride; Diabetes Mellitus, Experimental; gamma-Tocopherol; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Rabbits; Rats; Rats, Sprague-Dawley; Rats, Wistar; Ubiquinone; Vitamin A; Vitamin E Deficiency

Vitamin E has failed to protect humans from cardiovascular disease outcome, yet its role in experimental atherosclerosis remains less clear. A previous study (Proc. Natl. Acad. Sci. USA 97:13830-13834; 2000) showed that vitamin E deficiency caused by disruption of the alpha-tocopherol transfer protein gene (Ttpa) is associated with a modest increase in atherosclerosis in apolipoprotein E gene deficient (Apoe(-/-)) mice. Here we confirm this finding and report that in Apoe(-/-)Ttpa(-/-) mice dietary alpha-tocopherol (alphaT) supplements restored circulating and aortic levels of alphaT, and decreased atherosclerosis in the aortic root to a level comparable to that seen in Apoe(-/-) mice. However, such dietary supplements did not decrease disease in Apoe(-/-) mice, whereas dietary supplements with a synthetic vitamin E analog (BO-653), either alone or in combination with alphaT, decreased atherosclerosis in Apoe(-/-) and in Apoe(-/-)Ttpa(-/-) mice. Differences in atherosclerosis were not associated with changes in the arterial concentrations of F(2)-isoprostanes and cholesterylester hydro(pero)xides, nor were they reflected in the resistance of plasma lipids to ex vivo oxidation. These results show that vitamin E at best has a modest effect on experimental atherosclerosis in hyperlipidemic mice, and only in situations of severe vitamin E deficiency and independent of lipid oxidation in the vessel wall.

Topics: alpha-Tocopherol; Animals; Apolipoproteins E; Atherosclerosis; Benzofurans; Dietary Supplements; Lipid Peroxidation; Lipoproteins; Male; Mice; Mice, Transgenic; Oxidative Stress; Oxygen; Ubiquinone; Vitamin E; Vitamin E Deficiency