Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative modification of lipoproteins may trigger and maintain atherogenesis. We compared the effects of different antioxidants (alpha-tocopherol, probucol, ubiquinone-10) at doses similar to those used in humans in Watanabe Heritable Hyperlipidemic (WHHL) rabbits for 12 months. Aortic lesions were analyzed for their extent and cellular composition of lesions, mean thickness of fibrous caps and density of smooth muscle cells therein, content of antioxidants, non-oxidized and oxidized lipids. Compared to controls, probucol significantly lowered the extent and macrophage content of lesions and increased the existence and smooth muscle cell density of fibrous caps. alpha-Tocopherol supplementation increased the aortic content of vitamin E, but had no decreasing effect on either the accumulation of macrophage-specific antigen in the aorta or lesion size. Nevertheless, both probucol and alpha-tocopherol significantly decreased in vitro LDL oxidizability, measured under typically strong oxidative conditions. Ubiquinone-10 supplement increased lesion size and the fraction of lesions containing fibrous caps; however, LDL oxidizability remained unaffected by ubiquinone-10 treatment. None of the antioxidants tested lowered oxidized lipids within aortic tissue; however, long-term treatment with probucol provided the most effective anti-atherosclerotic effect, while alpha-tocopherol may be pro-atherogenic and ubiquinone-10 exerts ambivalent effects. Our data suggest that (i) widely used oxidation measures, such as ex-vivo LDL oxidizability, do not reflect the degree of atherosclerosis; and (ii) long-term beneficial effects of relatively low doses of antioxidants may be outweighed by high levels of plasma cholesterol in WHHL rabbits.
Atherosclerosis 2002 Aug
PMID:Comparison of the effects of alpha-tocopherol, ubiquinone-10 and probucol at therapeutic doses on atherosclerosis in WHHL rabbits. 1205 71

Therapeutic success of statins has distinctly established inhibition of de novo hepatic cholesterol synthesis as an effective approach to lower plasma LDL-cholesterol, the major risk factor for atherosclerosis and coronary heart disease. Statins inhibit HMG CoA reductase, a rate limiting enzyme which catalyses conversion of HMG CoA to mevalonic acid. However, in this process statins also inhibit the synthesis of several non-sterols e.g. dolichols and ubiquinone, which are implicated in side effects observed with statins. This prompted many major pharmaceutical companies in 1990s to target selective cholesterol synthesis beyond farnesyl pyrophosphate. The enzymes squalene synthetase, squalene epoxidase and oxidosqualene cyclase were identified as potential targets. Though inhibitors of these enzymes have been developed, till date no compound has been reported to have entered clinical trials. We evaluated the literature to understand merits and demerits of pursuing squalene epoxidase as a target for hypocholesterolemic drug development. Squalene epoxidase catalyses the conversion of squalene to 2,3-oxidosqualene. Although it has been extensively exploited for antifungal drug development, it has received little attention as a target for hypocholesterolemic drug design. This enzyme though recognized in the early 1970s was cloned 25 years later. This enzyme is an attractive step for pharmacotherapeutic intervention as it is the secondary rate limiting enzyme and blocking cholesterol synthesis at this step may result in accumulation of only squalene which is known to be stable and non toxic. Synthesis of several potent, orally bioavailable inhibitors of squalene epoxidase has been reported from Yamonuchi, Pierre Fabre and Banyu pharmaceuticals. Preclinical studies with these inhibitors have clearly demonstrated the potential of squalene epoxidase inhibitors as hypocholesterolemic agents. Hypochloesterolemic therapy is intended for prolonged duration and safety is an important determinant in clinical success. Lack of clinical trials, despite demonstrated preclinical efficacy by oral route, prompted us to evaluate safety concerns with squalene epoxidase inhibitors. In dogs, NB-598, a potent competitive squalene epoxidase inhibitor has been reported to exhibit signs of dermatitis like toxicity which has been attributed by some reviewers to accumulation of squalene in skin cells. Tellurium, a non-competitive inhibitor of squalene epoxidase has been associated with neuropathy in weanling rats. On the other hand, increased plasma levels of squalene in animals and humans (such as occurring subsequent to dietary olive oil or squalene administration) are safe and associated with beneficial effect such as chemoprevention and hypocholesterolemic activity. In our view, high circulating levels of squalene epoxidase inhibitor may be responsible for dermatitis and neuropathy. Competitive inhibition and pharmacokinetic profile minimizing circulating plasma levels (e.g. by hepatic sequestration and high first pass metabolism) could be important determinants in circumventing safety concerns of squalene epoxidase inhibitors. Recently, cholesterol-lowering effect of green tea has been attributed to potent squalene epoxidase inhibition, which can be consumed in much higher doses without toxicological effect. These facts strengthen optimism for developing clinically safe squalene epoxidase inhibitors. Put in perspective squalene epoxidase appears to be undervalued target which merits attention for development of better hypocholesterolemic drugs.
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PMID:Squalene epoxidase as hypocholesterolemic drug target revisited. 1246 39

Oxidized lipoproteins are implicated in atherosclerosis, and some antioxidants attenuate the disease in animals. Coenzyme Q(10) (CoQ(10)) in its reduced form, ubiquinol-10, effectively inhibits lipoprotein oxidation in vitro and in vivo; CoQ(10) supplements also inhibit atherosclerosis in apolipoprotein E gene knockout (apoE-/-) mice. Here we tested the effect of dietary CoQ(10) supplements on intimal proliferation and lipoprotein lipid oxidation in balloon-injured, hypercholesterolemic rabbits. Compared to nonsupplemented chow, CoQ(10) supplementation (0.5% and 1.0%, w/w) significantly increased the plasma concentration of CoQ(10) and the resistance of plasma lipids to ex vivo oxidation. CoQ(10) supplements also increased the content of CoQ(10) in the aorta and liver, but not in the brain, skeletal muscle, kidney, and heart. Surprisingly, CoQ(10) supplementation at 1% increased the aortic concentrations of all lipids, particularly triacylglycerols, although it significantly inhibited the proportion of triacylglycerols present as hydroperoxides by > 80%. The observed increase in vessel wall lipid content was reflected in elevated plasma concentrations of cholesterol, cholesteryl esters and triacylglycerols, and hepatic levels of mRNA for 3-hydroxy-3-methylglutaryl-coenzyme A reductase. CoQ(10) supplements did not attenuate lesion formation, assessed by the intima-to-media ratio of injured aortic vessels. Thus, like in apoE-/- mice, a high dose of supplemented CoQ(10) inhibits lipid oxidation in the artery wall of balloon-injured, hypercholesterolemic rabbits. However, unlike its antiatherosclerosis activity in the mice, CoQ(10) does not inhibit intimal hyperplasia in rabbits, thereby dissociating this disease process from lipid oxidation in the vessel wall.
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PMID:Coenzyme Q(10) supplementation inhibits aortic lipid oxidation but fails to attenuate intimal thickening in balloon-injured New Zealand white rabbits. 1288 92

The oxidative modification of low density lipoprotein (LDL) is thought to play an important role in atherogenesis. Drugs of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) family are usually used as a very effective lipid-lowering preparations but they simultaneously block biosynthesis of both cholesterol and ubiquinone Q10 (coenzyme Q), which is an intermediate electron carrier in the mitochondrial respiratory chain. It is known that reduced form of ubiquinone Q10 acts in the human LDL as very effective natural antioxidant. Daily per os administration of HMG-CoA reductase inhibitor simvastatin to rats for 30 day had no effect on high-energy phosphates (adenosin triphosphate, creatine phosphate) content in liver but decreased a level of these substances in myocardium. We study the Cu2+-mediated susceptibility of human LDL to oxidation and the levels of free radical products of LDL lipoperoxidation in LDL particles from patients with atherosclerosis after 3 months treatment with natural antioxidants vitamin E as well as during 6 months administration of HMG-CoA reductase inhibitors such as pravastatin and cerivastatin in monotherapy and in combination with natural antioxidant ubiquinone Q10 or synthetic antioxidant probucol in a double-blind placebo-controlled trials. The 3 months of natural antioxidant vitamin E administration (400 mg daily) to patients did not increase the susceptibility of LDL to oxidation. On the other hand, synthetic antioxidant probucol during long-time period of treatment (3-6 months) in low-dose (250 mg daily) doesn't change the lipid metabolism parameters in the blood of patients but their high antioxidant activity was observed. Really, after oxidation of probucol-contained LDL by C-15 animal lipoxygenase in these particles we identified the electron spin resonance signal of probucol phenoxyl radical that suggests the interaction of LDL-associated probucol with lipid radicals in vivo. We observed that 6 months treatment of patients with pravastatine (40 mg daily) or cerivastatin (0.4 mg daily) was followed by sufficiently accumulation of LDL lipoperoxides in vivo. In contrast, the 6 months therapy with pravastatin in combination with ubiquinone Q10 (60 mg daily) sharply decreased the LDL initial lipoperoxides level whereas during treatment with cerivastatin in combination with probucol (250 mg daily) the LDL lipoperoxides concentration was maintained on an invariable level. Therefore, antioxidants may be very effective in the prevention of atherogenic oxidative modification of LDL during HMG-CoA reductase inhibitors therapy.
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PMID:Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins. 1295 8

Although not currently indicated for chronic heart failure (CHF), statins have been associated with improved outcome in retrospective analysis. However, statin therapy reduces plasma levels of coenzyme Q(10) (ubiquinone), which may have adverse effects on heart failure states. We hypothesized that atorvastatin treatment improves endothelial function in patients with chronic heart failure independent of LDL-cholesterol alterations. Furthermore, we assessed how reductions in coenzyme Q(10) levels impact on potentially improved endothelial function. Twenty-four patients with stable, symptomatic heart failure (New York Heart Association Class II or III) and a left ventricular ejection fraction <40% were randomised to 40 mg atorvastatin or placebo for 6 weeks and crossed over to the other treatment arm for a further 6 weeks, after a 2-week wash out. Forearm resistance vessel function was assessed by venous occlusion plethysmography during infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and N(G)-monomethyl-L-arginine (L-NMMA) into the brachial artery. Atorvastatin treatment lowered triglycerides, LDL-cholesterol and coenzyme Q(10) levels (all p<0.001) and improved endothelium-dependent vasodilatation during acetylcholine infusion (p=0.015). Endothelium-dependent forearm blood flow improvements correlated with reductions in coenzyme Q(10) levels (p=0.011), but not with LDL-cholesterol levels (p=0.084). Coenzyme Q(10) remained the significant variable predicting improvement in NO dependent endothelial function after adjusting for LDL-cholesterol levels (p=0.041). In conclusion, short-term atorvastatin therapy improved endothelial function in chronic heart failure patients. Further studies are required to determine whether coenzyme Q(10) reductions are limiting the maximum favourable effects of statin therapy on the microcirculation.
Atherosclerosis 2005 Mar
PMID:Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure. 1572 Oct 28

Mevalonate pathway is an important metabolic pathway which plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme-A, isopentenyl tRNA and ubiquinone. While extensively studied in regard with cholesterol synthesis and its implications in cardiovascular diseases, in recent years the mevalonate pathway has become a challenging and, in the meantime, fascinating topic, when a large number of experimental and clinical studies suggested that inhibition of non-sterol isoprenoids might have valuable interest in human pathology. These molecules that are essential for cell growth and differentiation appear to be potential interesting therapeutic targets for many areas of ongoing research: oncology, autoimmune disorders, atherosclerosis, and Alzheimer disease. Also, considerable progress has been made in the past decade in understanding the pathophysiology of two auto-inflammatory disorders resulting from an inherited deficiency of mevalonate kinase, the first committed enzyme of the mevalonate pathway. Here we present a brief description of the biochemistry of the mevalonate pathway, together with a review of the current knowledge of the clinical and therapeutical implications of this fascinating and complex metabolic pathway.
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PMID:Mevalonate pathway: a review of clinical and therapeutical implications. 1746 79

Coenzyme Q10 (ubiquinone) is a mitochondrial coenzyme which is essential for the production of ATP. Being at the core of cellular energy processes it assumes importance in cells with high energy requirements like the cardiac cells which are extremely sensitive to CoQ10 deficiency produced by cardiac diseases. CoQ10 has thus a potential role for prevention and treatment of heart ailments by improving cellular bioenergetics. In addition it has an antioxidant, a free radical scavenging and a vasodilator effect which may be helpful in these conditions. It inhibits LDL oxidation and thus the progression of atherosclerosis. It decreases proinflammatory cytokines and decreases blood viscosity which is helpful in patients of heart failure and coronary artery disease. It also improves ischemia and reperfusion injury of coronary revascularisation. Significant improvement has been observed in clinical and hemodynamic parameters and in exercise tolerance in patients given adjunctive CoQ10 in doses from 60 to 200 mg daily in the various trials conducted in patients of heart failure, hypertension, ischemic heart disease and other cardiac illnesses. Recently it has been found to be an independent predictor of mortality in congestive heart failure. It has also been found to be helpful in vertigo and Meniere-like syndrome by improving the immune system. Further research is going on to establish firmly its role in the therapy of cardiovascular diseases.
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PMID:Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. 1963 84

Atherosclerotic cardiovascular disease is the leading cause of mortality in the Western world. Dysfunction of the mitochondrial respiratory chain and overproduction of reactive oxygen species (ROS) are associated with atherosclerosis and cardiovascular disease. Oxidation increases the atherogenecity of LDL. Oxidized LDL may be apoptotic or nonapoptotic for vascular endothelial cells (EC), depending on the intensity of oxidation. A previous study demonstrated that nonapoptotic oxidized LDL increased activity of mitochondrial complex I in human umbilical vein EC. The present study examined the impact of extensively oxidized LDL (eoLDL) on oxygen consumption and the activities of key enzymes in the mitochondrial respiratory chain of cultured porcine aortic EC. Oxygraphy detected that eoLDL significantly reduced oxygen consumption in various mitochondrial complexes. Treatment with eoLDL significantly decreased NADH-ubiquinone dehydrogenase (complex I), succinate cytochrome c reductase (complex II/III), ubiquinone cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV) activities and the NAD+-to-NADH ratio in EC compared with mildly oxidized LDL, LDL, or vehicle. Butylated hydroxytoluene, a potent antioxidant, normalized eoLDL-induced reductions in complex I and III enzyme activity in EC. Mitochondria-associated intracellular ROS and release of ROS from EC were significantly increased after eoLDL treatment. These findings suggest that eoLDL impairs enzyme activity in mitochondrial respiratory chain complexes and increases ROS generation from mitochondria of arterial EC. Collectively, these effects could contribute to vascular injury and atherogenesis under conditions of hypercholesterolemia and oxidative stress.
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PMID:Effects of extensively oxidized low-density lipoprotein on mitochondrial function and reactive oxygen species in porcine aortic endothelial cells. 1984 72

Coenzyme Q (CoQ), a lipophilic cofactor of the electron transport chain in the mitochondria, can be synthesized endogenously or provided by food. The aim of this review is to summarize the in vitro cell culture studies, the in vivo animal studies, and the human studies investigating the impact of CoQ supplementation on the occurrence of obesity and related disorders (diabetes, hypertension, lipemia, and atherosclerosis). The antioxidative properties of CoQ have been observed in different experimental models of atherosclerosis, obesity, and diabetes. The recent discovery of the anti-inflammatory effect of CoQ, mostly described in vitro, has generated increased interest in CoQ supplementation, but it needs to be confirmed in vivo in pathological situations. CoQ intervention studies in humans failed to show reproducible effects on body weight, fat mass, or glycemia, but CoQ supplementation does seem to have an antihypertensive effect. The molecular mechanism to explain this effect has only recently been discovered.
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PMID:Is there a place for coenzyme Q in the management of metabolic disorders associated with obesity? 2311 Jun 42

Coenzyme Q(10), a lipid soluble benzoquinone, has excellent antioxidant and membrane stabilizing properties in the cardiac tissue. The present study quantitatively investigated the effects of coenzyme Q(10) on in vitro LDL oxidation. The formation of conjugated dienes, malondialdehyde (MDA) and electrophoretic mobility were monitored as markers of the oxidation of LDL, respectively. Coenzyme Q(10) showed a decrease the formation of conjugated dienes and MDA, respectively, against oxidation in vitro. Coenzyme Q(10) also reduced electrophoretic mobility of the oxidized human LDL. Thus, results showed that the coenzyme Q(10) exhibits strong antioxidant activity in CuSO(4)-mediated oxidation of LDL (P<0.05) in vitro. The inhibitory effects of the coenzyme Q(10) on LDL oxidation were dose-dependent at concentrations ranging from 20 nM to 300 nM. Moreover, the effects of coenzyme Q(10) on LDL oxidation were compared with vitamin E and vitamin C. This study showed that coenzyme Q(10) is a potent antioxidant to protect LDL against oxidation in vitro and may be a good alternative to reduce the risk of atherosclerosis and coronary heart disease and other free radical associated health problems.
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PMID:Effects of coenzyme Q(10) on LDL oxidation in vitro. 2345 79


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