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Ubiquinol-10 Protects Human Low Density Lipoprotein More Efficiently Against Lipid Peroxidation Than Does ALPHA-Tocopherol
Abstract
The temporal disappearance of natural antioxidants associated with human low density lipoprotein (LDL) in relation to the appearance of various classes of lipid hydroperoxides was investigated under three types of oxidizing conditions. Freshly isolated LDL from plasma of healthy subjects was free of detectable amounts of lipid hydroperoxides as measured by HPLC postcolumn chemiluminescence detection. Exposure of such LDL to a mild, constant flux of aqueous peroxyl radicals led to rapid and complete oxidation of ubiquinol-10, followed by slower partial depletion of lycopene, beta-carotene, and alpha-tocopherol. After an initial lag period of complete inhibition of detectable lipid peroxidation, formation of hydroperoxides of cholesterol esters, triglycerides, and phospholipids was observed. The onset of detectable lipid peroxidation corresponded closely with the completion of ubiquinol-10 consumption. However, small amounts of ascorbate, present as a contaminant in the LDL preparation, rather than ubiquinol-10 itself were responsible for the initial lag period. Thus, complete consumption of ubiquinol-10 was preceded by that of ascorbate, and exposure of ascorbate-free LDL to aqueous peroxyl radicals resulted in immediate formation of detectable amounts of lipid hydroperoxides. The rate of radical-mediated formation of lipid hydroperoxides in ascorbate-free LDL was low as long as ubiquinol-10 was present, but increased rapidly after its consumption, even though more than 80% and 95% of endogenous carotenoids and alpha-tocopherol, respectively, were still present. Qualitatively similar results were obtained when peroxyl radicals were generated within LDL or when the lipoprotein was exposed to oxidants produced by activated human polymorphonuclear leukocytes. LDL oxidation was reduced significantly by supplementing the lipoprotein preparation with physiological amounts of either ascorbate or ubiquinol-10. Our data show that ubiquinol-10 is much more efficient in inhibiting LDL oxidation than either lycopene, beta-carotene, or alpha-tocopherol.
... The cardiovascular protective effect of CoQ10 supplementation is described extensively in the literature (for a review see [72,73]). It is generally accepted that elevated levels of oxidized low-density lipoproteins (LDLs) are a risk factor for cardiovascular disease (CVD), and it is known that reduced CoQ10 protects human LDL from lipid peroxidation [74]. Interestingly, Takahashi and colleagues have shown that a CoQ10 reductase on the outer surface of liver cells can help maintain the reduced state of extracellular CoQ10 and thus prevent LDL oxidation [75]. ...
CDKL5 deficiency disorder (CDD), a developmental encephalopathy caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, is characterized by a complex and severe clinical picture, including early-onset epilepsy and cognitive, motor, visual, and gastrointestinal disturbances. This disease still lacks a medical treatment to mitigate, or reverse, its course and improve the patient’s quality of life. Although CDD is primarily a genetic brain disorder, some evidence indicates systemic abnormalities, such as the presence of a redox imbalance in the plasma and skin fibroblasts from CDD patients and in the cardiac myocytes of a mouse model of CDD. In order to shed light on the role of oxidative stress in the CDD pathophysiology, in this study, we aimed to investigate the therapeutic potential of Coenzyme Q10 (CoQ10), which is known to be a powerful antioxidant, using in vitro and in vivo models of CDD. We found that CoQ10 supplementation not only reduces levels of reactive oxygen species (ROS) and normalizes glutathione balance but also restores the levels of markers of DNA damage (γ-H2AX) and senescence (lamin B1), restoring cellular proliferation and improving cellular survival in a human neuronal model of CDD. Importantly, oral supplementation with CoQ10 exerts a protective role toward lipid peroxidation and DNA damage in the heart of a murine model of CDD, the Cdkl5 (+/−) female mouse. Our results highlight the therapeutic potential of the antioxidant supplement CoQ10 in counteracting the detrimental oxidative stress induced by CDKL5 deficiency.
... sons behind this action suggested that the peroxidation is propagated within lipoprotein particles by reaction of the Vitamin E radical (for example α-tocopheroxyl radical) with polyunsaturated fatty acid moieties in the lipid. In another study, the presence of co-antioxidants such as vitamin C and ubiquinol prevent vitamin E pro-oxidative actions (Stocker et. al, 1991). ...
... In other words, the concentration-dependent inversion of the antioxidant effect is possible, which was observed both in vitro [78] and in vivo [77]. Similar to other liposoluble vitamins, α-TOH is transported within the hydrophobic lipid core of LDL particles [79], although defense of circulating LDL against FRO is performed not by α-TOH, but by the reduced (phenolic) form of coenzyme Q 10 [80][81][82][83]. Remembering that one LDL particle contains no more than 1-2 molecules of coenzyme Q 10 per about 800 molecules of FRO substrate, i.e., unsaturated phospholipids [84], effective inhibition of FRO in LDL by this antioxidant is possible only with its efficient reduction (biogeneration), which occurs, probably, with the participation of radical intermediates α-TOH and ascorbate [85][86][87][88]. ...
This review summarises the data from long-term experimental studies and literature data on the role of oxidatively modified low-density lipoproteins (LDL) in atherogenesis and diabetogenesis. It was shown that not “oxidized” (lipoperoxide-containing) LDL, but dicarbonyl-modified LDL are atherogenic (actively captured by cultured macrophages with the help of scavenger receptors), and also cause expression of lectin like oxidized low density lipoprotein receptor 1 (LOX-1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX-1) genes in endotheliocytes, which stimulate apoptosis and endothelial dysfunction. The obtained data allowed us to justify new approaches to pharmacotherapy of atherosclerosis and diabetes mellitus.
... Previous studies revealed that the redox status of CoQ10, CoQ10-H 2 , is the first-line defense antioxidant in LDL [27], and the plasma concentration of redox form of CoQ10 can increase to two times by a single oral administration of 100 or 200 mg of CoQ10 [28]. In addition, the redox form of CoQ10 evaluated by high-performance liquid chromatography (HPLC) with UV detection and also electrochemical detection was decreased in 35 FCH patients with an overall dense LDL profile compared with buoyant LDL profile [29]. ...
Purpose of Review
Currently, the preventive and treatment strategies for metabolic disorders are not fully effective, and many limitations remain with these tools. Coenzyme Q10 (CoQ10) is a new promising antioxidant and anti-inflammatory option that can target the mechanisms involved in the progression of metabolic disorders. The purpose of this study was to assess and summarize the implication of CoQ10 in diabetes, hyperlipidemia, and kidney disease.
Recent Findings
Emerging evidence indicated that CoQ10 is effective for familial hypercholesterolemia, familial combined hyperlipidemia, hypercholesterolemia-induced atherosclerosis and cardiac damage, hypercholesterolemia-induced Alzheimer’s-like disease, Type 2 diabetes mellitus, diabetic nephropathy, and metabolic-associated liver disease.
Summary
CoQ10 could be a novel agent for the treatment of metabolic disorders including diabetes and its complications, several forms of hyperlipidemia, and metabolic-associated liver disease.
... 54 A study on lipid peroxidation revealed that in the early stages of oxidation processes, ubiquinol acts as a highly effective antioxidant, protecting cell membrane lipids and circulatory lipoproteins. 55 CoQ10 exhibits both direct and indirect antioxidant properties. Directly, it interacts with and scavenges free radicals. ...
Introduction: It is well-established that oxidative stress is deeply involved in myocardial ischemia-reperfusion injury. Considering the potent antioxidant properties of coenzyme Q10 (CoQ10), we aimed to assess whether CoQ10 supplementation could exert beneficial effects on plasma levels of oxidative stress biomarkers in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPIC). Methods: Seventy patients with the first attack of STEMI, eligible for PPCI were randomly assigned to receive either standard treatments plus CoQ10 (400 mg before PPCI and 200 mg twice daily for three days after PPCI) or standard treatments plus placebo. Plasma levels of oxidative stress biomarkers, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured at 6, 24, and 72 hours after completion of PPCI. Results: The changes in plasma levels of the studied biomarkers at 6 and 24 hours after PPCI were comparable in the both groups (P values>0.05). This is while at 72 hours, the CoQ10- treated group exhibited significantly higher plasma levels of SOD (P value<0.001), CAT (P value=0.001), and TAC (P value<0.001), along with a lower plasma level of MDA (P value=0.002) compared to the placebo-treated group. The plasma activity of GPX showed no significant difference between the groups at all the study time points (P values>0.05). Conclusion: This study showed that CoQ10 has the potential to modulate the balance between antioxidant and oxidant biomarkers after reperfusion therapy. Our results suggest that CoQ10, through its antioxidant capacity, may help reduce the reperfusion injury in ischemic myocardium.
Tocotrienols, a group of vitamin E molecules, are natural dietary compounds that are abundant in rice bran oil, palm oil, and annatto oil but are also found in unrefined cereal grains, wheat germ, rye, oat, barley, amaranth, safflower, and seeds of pumpkin, grape, and flax. Varied numbers and locations of methyl groups on the chromanol ring, yields four different tocotrienol forms of alpha (α), beta (β), delta (δ), or gamma (γ). Tocotrienols are powerful antioxidants that exert anti-inflammatory, anti-cancer, neuroprotective, and cholesterol lowering properties which are often not demonstrated by tocopherols, the other class of the vitamin E family. The Etiology of atherosclerosis, the major cause of cardiovascular disease (CVD), is strongly associated with chronic inflammation as well as an abnormal metabolism, regulation, and expression of cholesterol. Tocotrienols show strong potential to hinder fat oxidation and inflammation for protection of arterial walls from atherosclerotic damage. Studies have shown that tocotrienol supplementation can increase the efflux of low density lipoprotein (LDL) by inducing expression of LDL receptors. By suppressing the upstream transcriptional regulators of lipid homeostasis genes, tocotrienols can also reduce the endogenous synthesis of cholesterol, very low density lipoprotein (VLDL), and triglycerides. Additionally, these vitamers can stimulate ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) which is the rate-limiting enzyme of the cholesterol biosynthesis pathway. Pleiotropic properties of tocotrienols render these vitamins protective and therapeutic effects against many chronic diseases including cardiovascular diseases.
Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid sidechain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) and in several other cellular processes. In fact, CoQ appears to be central to the redox balance of the cell. Remarkably, its structure and properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox active molecule in the ETC and other enzymatic systems, its role as a pro-oxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.
After exposure to low density lipoprotein (LDL) that had been minimally modified by oxidation (MM-LDL), human endothelial cells (EC) and smooth muscle cells (SMC) cultured separately or together produced 2- to 3-fold more monocyte chemotactic activity than did control cells or cells exposed to freshly isolated LDL. This increase in monocyte chemotactic activity was paralleled by increases in mRNA levels for a monocyte chemotactic protein 1 (MCP-1) that is constitutively produced by the human glioma U-105MG cell line. Antibody that had been prepared against cultured baboon smooth muscle cell chemotactic factor (anti-SMCF) did not inhibit monocyte migration induced by the potent bacterial chemotactic factor f-Met-Leu-Phe. However, anti-SMCF completely inhibited the monocyte chemotactic activity found in the media of U-105MG cells, EC, and SMC before and after exposure to MM-LDL. Moreover, monocyte migration into the subendothelial space of a coculture of EC and SMC that had been exposed to MM-LDL was completely inhibited by anti-SMCF. Anti-SMCF specifically immunoprecipitated 10-kDa and 12.5-kDa proteins from EC. Incorporation of [35S]methionine into the immunoprecipitated proteins paralleled the monocyte chemotactic activity found in the medium of MM-LDL stimulated EC and the levels of MCP-1 mRNA found in the EC. We conclude that (i) SMCF is in fact MCP-1 and (ii) MCP-1 is induced by MM-LDL.
The rate and products of oxidation of methyl linoleate dispersed in water by Triton X-100 were measured at 50 degree C. The oxidation was initiated by water- or oil-soluble azo-initiators. The oxidation proceeded smoothly by both types of initiators without any noticeable induction period and a constant rate of oxygen uptake was observed. Conjugated diene hydroperoxides were formed almost quantitatively. The oxidizability for methyl linoleate in aqueous dispersion was obtained as k//p/(2k//t)** one-half equals 0. 032 (s multiplied by (times) mol/L-oil)** minus ** one-half where k//p and k//t are the rate constants for propagation and termination reactions, respectively.
The activity of uric acid as a chain-breaking antioxidant was studied in the oxidations of methyl linoleate micelles and soybean phosphatidylcholine liposomes in aqueous dispersions at 37°C. Uric acid was found to act as a radical scavenger. Uric acid located in an aqueous phase could trap the radicals in an aqueous phase, but it could not scavenge radicals within the lipid region of micelles and liposomal membranes. The kinetics of the oxidations of lipids in aqueous dispersions inhibited by uric acid was discussed.
Considerations sur les difficultes de mesures de la cinetique d'autooxydation. Cas de l'autooxydation de linoleique dans des micelles de laurysulfate de sodium et de l'autooxydation des couches multimoleculaires de dilinoleoyl phosphatidylcholine
A fast single-step lipid extraction procedure and high-performance liquid chromatography with in-line uv and electrochemical detection are used for the simultaneous quantitative determination of tocopherols, ubiquinols, and ubiquinones in blood, plasma, tissue homogenates, and subcellular fractions. The compounds of interest can be quantitatively extracted into hexane from a sodium dodecyl sulfate-treated aqueous homogenate after precipitation of protein by addition of an equal volume of ethanol. α-, γ-, and δ-Tocopherol, ubiquinol 9, ubiquinol 10, and ubiquinones 9 and 10 can be well separated on a reversed phase column. Ubiquinones are detected at 275 nm by the uv detector, and ubiquinols and tocopherols by the electrochemical detector in the oxidative mode. Quantitation is done by comparing chromatographic peak heights to those of a standard solution containing known amounts of tocopherols, ubiquinols 9 and 10, and ubiquinones 9 and 10, analyzed under identical conditions. The high sensitivity of the electrochemical detection allows operation at low potentials (+0.5 V) with low detector response, but high selectivity for the easily oxidizable tocopherols and ubiquinols and decreased baseline noise. The uv detection limits the overall sensitivity of the procedure to 2 pmol ubiquinone, corresponding to 0.1 μm ubiquinone in the lipid extract. The ranges of values obtained for rat and guinea pig tissues, for rat liver mitochondria, and for blood and plasma from rats and humans are given.
An assay for the separation and detection of lipid hydroperoxides and hydrogen peroxide in biological samples using HPLC and isoluminol chemiluminescence was recently described (Y. Yamamoto, M. H. Brodsky, J. C. Baker, and B. N. Ames (1987)Anal. Biochem.160, 7–13; Y. Yamamoto and B. N. Ames (1987)Free Rad. Biol. Med.3, 359–361). In this paper the application of this assay to the analysis of human blood plasma is described in detail, and three compounds producing chemiluminescence that were observed in the initial studies in plasma extracted with methanol and hexane are further characterized. It is shown that various lipid hydroperoxides added to plasma are detected by the assay. In contrast, hydrogen peroxide added to plasma is rapidly degraded by endogenous catalase. Hydrogen peroxide and a second, minor compound producing chemiluminescence, which appear in the assay of the methanol and the hexane extract of plasma, respectively, appear to be generated during analysis and are not likely to be present in plasma. The third compound yielding a chemiluminescence peak, which is extracted into the hexane phase of plasma and was earlier assigned to cholesterol ester hydroperoxide, is shown to be neither a cholesterol ester nor a hydroperoxide, but the hydroquinone ubiquinol-10. As the chemiluminescence response of hydroperoxides, but not of hydroquinones, is eliminated by reducing reagents such as sodium borohydride or triphenylphosphine, such reduction should be used to confirm that any chemiluminescence producing lipid observed in the assay is a hydroperoxide, not a hydroquinone. We conclude that isolated human plasma from healthy subjects is very unlikely to contain hydrogen peroxide in concentrations greater than about 0.25 μm and does not contain lipid hydroperoxides in concentrations greater than 0.03 μm. The method described, when used with appropriate precautions, is a convenient and very sensitive assay for lipid hydroperoxides in biological tissues.
Oxidized lipoproteins have been identified in atherosclerotic plaques and in early lesions in humans as well as in animals. There is accumulating evidence that such oxidized lipoproteins have an important role in atherosclerosis. Treatment of endothelial cells with altered lipoproteins stimulates monocyte binding as well as the production of chemotactic factors for monocytes. Both these findings could be relevant to the accumulation of monocytes-macrophages in the arterial wall during the early stages of lesion development. We now report that treatment of endothelial cells (EC) with modified low-density lipoproteins obtained by mild iron oxidation or by prolonged storage, results in a rapid and large induction of the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage CSF (M-CSF) and granulocyte CSF (G-CSF). These growth factors affect the differentiation, survival, proliferation, migration and metabolism of macrophages/granulocytes, and G-CSF and GM-CSF also affect the migration and proliferation of EC. Because EC and macrophages are important in the development of atherosclerosis, the expression of the CSFs by these cells could contribute to the disease.
Published experimental data pertaining to the participation of coenzyme Q as a site of free radical formation in the mitochondrial electron transfer chain and the conditions required for free radical production have been reviewed critically. The evidence suggests that a component from each of the mitochondrial NADH-coenzyme Q, succinate-coenzyme Q, and coenzyme QH2-cytochrome c reductases (complexes I, II, and III), most likely a nonheme iron-sulfur protein of each complex, is involved in free radical formation. Although the semiquinone form of coenzyme Q may be formed during electron transport, its unpaired electron most likely serves to aid in the dismutation of superoxide radicals instead of participating in free radical formation. Results of studies with electron transfer chain inhibitors make the conclusion dubious that coenzyme Q is a major free radical generator under normal physiological conditions but may be involved in superoxide radical formation during ischemia and subsequent reperfusion. Experiments at various levels of organization including subcellular systems, intact animals, and human subjects in the clinical setting, support the view that coenzyme Q, mainly in its reduced state, may act as an antioxidant protecting a number of cellular membranes from free radical damage.
Oxidative modification of LDL is accompanied by a number of compositional and structural changes, including increased electrophoretic mobility, increased density, fragmentation of apolipoprotein B, hydrolysis of phosphatidylcholine, derivatization of lysine amino groups, and generation of fluorescent adducts due to covalent binding of lipid oxidation products to apo B. In addition, oxidation of LDL has been shown to result in numerous changes in its biologic properties that could have pathogenetic importance, including accelerated uptake in macrophages, cytotoxicity, and chemotactic activity for monocytes. The present article summarizes very recent developments related to the mechanism of oxidation of LDL by cells, receptor-mediated uptake of oxidized LDL in macrophages, the mechanism of phosphatidylcholine hydrolysis during LDL oxidation, and other biologic actions of oxidized LDL including cytotoxicity, altered eicosanoid metabolism, and effects on the secretion of growth factors and chemotactic factors. In addition, this review will examine the evidence for the presence of oxidized LDL in vivo and the evidence that oxidized LDL plays a pathogenetic role in atherosclerosis.
Ubiquinones (CoQn) are intrinsic lipid components of many membranes. Besides their role in electron-transfer reactions they may act as free radical scavengers, yet their antioxidant function has received relatively little study. The efficiency of ubiquinols of varying isoprenoid chain length (from Q0 to Q10) in preventing (Fe2+ + ascorbate)-dependent or (Fe2+ + NADPH)-dependent lipid peroxidation was investigated in rat liver microsomes and brain synaptosomes and mitochondria. Ubiquinols, the reduced forms of CoQn, possess much greater antioxidant activity than the oxidized ubiquinone forms. In homogenous solution the radical scavenging activity of ubiquinol homologues does not depend on the length of their isoprenoid chain. However in membranes ubiquinols with short isoprenoid chains (Q1-Q4) are much more potent inhibitors of lipid peroxidation than the longer chain homologues (Q5-Q10). It is found that: i) the inhibitory action, that is, antioxidant efficiency of short-chain ubiquinols decreases in order Q1 greater than Q2 greater than Q3 greater than Q4; ii) the antioxidant efficiency of long-chain ubiquinols is only slightly dependent on their concentrations in the order Q5 greater than Q6 greater than Q7 greater than Q8 greater than Q9 greater than Q10 and iii) the antioxidant efficiency of Q0 is markedly less than that of other homologues. Interaction of ubiquinols with oxygen radicals was followed by their effects on luminol-activated chemiluminescence. Ubiquinols Q1-Q4 at 0.1 mM completely inhibit the luminol-activated NADPH-dependent chemiluminescent response of microsomes, while homologues Q6-Q10 exert no effect. In contrast to ubiquinol Q10 (ubiquinone Q10) ubiquinone Q1 synergistically enhances NADPH-dependent regeneration of endogenous vitamin E in microsomes thus providing for higher antioxidant protection against lipid peroxidation. The differences in the antioxidant potency of ubiquinols in membranes are suggested to result from differences in partitioning into membranes, intramembrane mobility and non-uniform distribution of ubiquinols resulting in differing efficiency of interaction with oxygen and lipid radicals as well as different efficiency of ubiquinols in regeneration of endogenous vitamin E.