Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases (original) (raw)
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Effects of statins on oxidative stress
Biological Trace Element Research, 2004
Free oxygen radicals and insufficient antioxidant enzymes have been implicated in the pathogenesis of hypercholesterolemia (HC). Trace elements function as cofactors in antioxidant enzymes. Antioxidant system and trace elements were investigated in many different studies including HC, but these subjects have not been investigated as a whole in these patients. The aim of the present study was to investigate the antioxidative system and trace elements in hypercholesterolemic patients given fluvastatin therapy.
Redox Report, 2007
Accumulating evidence links hypertension and atherosclerotic vascular disease with the accumulation of oxidized, low-density lipoproteins and enhanced generation of reactive oxygen species (ROS) in the vessel wall. 1-3 ROS are generated as by-products of metabolism and rapidly react with cellular components, causing damage to membrane lipids, proteins and DNA. Endothelial cells generate superoxide anions (O 2 •-) and H 2 O 2 from xanthine oxidase, peroxidases, lipoxygenase, cyclooxygenase, nitric oxide synthase and NAD(P)H oxidases. 3 In atherosclerosis, accumulation of low-density lipoprotein (LDL), cholesterol and lipid deposits in the vessel wall lead to endothelial dysfunction, smooth muscle cell proliferation and fibrosis and lumen occlusion over decades. 2 Oxidation of arachidonic acid, a (ω-6) polyunsaturated fatty acid in LDL and cell membranes, can lead to the formation of cytotoxic aldehydes such as 4-hydroxy-2-nonenal (HNE), which further exacerbate atherogenesis through modification of ε-lysine residues in apolipoprotein B-100 of LDL leading to uptake by macrophages. Atherosclerotic lesions in humans and animal models contain high levels of HNE and amino acid adducts, making it a useful biomarker of lipid peroxidation and oxidative damage to proteins. 5,6 Moreover, recent evidence has shown that HNE can directly modulate intracellular signalling pathways, including mitogen-activated protein kinases (MAPK) and the transcription factors activator protein-1 (AP-1), nuclear factor-κB, (NF-κB) and NF-E2-related factor-2 (Nrf2). 7-9 In this context, HNE represents an important mediator of redox signalling in cells, either
The Role of the Nrf2/ARE Antioxidant System in Preventing Cardiovascular Diseases
Diseases, 2016
It is widely believed that consuming foods and beverages that have high concentrations of antioxidants can prevent cardiovascular diseases and many types of cancer. As a result, many articles have been published that give the total antioxidant capacities of foods in vitro. However, many antioxidants behave quite differently in vivo. Some of them, such as resveratrol (in red wine) and epigallocatechin gallate or EGCG (in green tea) can activate the nuclear erythroid-2 like factor-2 (Nrf2) transcription factor. It is a master regulator of endogenous cellular defense mechanisms. Nrf2 controls the expression of many antioxidant and detoxification genes, by binding to antioxidant response elements (AREs) that are commonly found in the promoter region of antioxidant (and other) genes, and that control expression of those genes. The mechanisms by which Nrf2 relieves oxidative stress and limits cardiac injury as well as the progression to heart failure are described. Also, the ability of statins to induce Nrf2 in the heart, brain, lung, and liver is mentioned. However, there is a negative side of Nrf2. When over-activated, it can cause (not prevent) cardiovascular diseases and multi-drug resistance cancer.
Antioxidant effects of statins in the management of cardiometabolic disorders
Journal of atherosclerosis and thrombosis, 2014
Redox systems are key players in vascular health. A shift in redox homeostasis-that results in an imbalance between reactive oxygen species (ROS) generation and endogenous antioxidant defenses has the potential to create a state of oxidative stress that subsequently plays a role in the pathogenesis of a number of diseases, including those of the cardiovascular and metabolic system. Statins, which are primarily used to reduce the concentration of low-density lipoprotein cholesterol, have also been shown to reduce oxidative stress by modulating redox systems. Studies conducted both in vitro and in vivo support the role of oxidative stress in the development of atherosclerosis and cardiovascular diseases. Oxidative stress may also be responsible for various diabetic complications and the development of fatty liver. Statins reduce oxidative stress by blocking the generation of ROS and reducing the NAD+/NADH ratio. These drugs also have effects on nitric oxide synthase, lipid peroxidatio...
Vascular Pharmacology, 2013
Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), are important lipid-lowering agents. After two decades of laboratory and clinical studies, their pleiotropic effects appear well-established. One of these effects is through the regulation of Rac1 and NADPH oxidases. Relatively few human trials have been carried out with regards to the action of statins on Rac1 and NADPH oxidases, but similar positive effects were also observed in blood vessels and myocardium of participants in the trials. Besides, more specific biomarkers for the antioxidation effects of statins have been developed in the recent two years; both monitoring of the progress of disease and the effects of medical therapy will be possible. Further development of the potency and specificity of statin may enhance their therapeutic potential on cardiovascular disease.
A comparative study of the in vitro antioxidant activity of statins
International Journal of Cardiology, 2003
Background: Treatment of hypercholesterolemia with statins is remarkably effective in cardiovascular prevention. This has led to the hypothesis that these drugs may act on the atherosclerotic plaque by mechanism(s) independent of the reduction of serum cholesterol levels. The aim of this study was to assess the total antioxidant activity of the most prescribed statins: fluvastatin, atorvastatin, pravastatin and simvastatin. Methods: We measured the in vitro antioxidant activity of statins as their ability to antagonize the oxidation of a-keto-g-methiolbutyric acid by both hydroxyl and peroxyl radicals. The results are expressed as Total Oxyradical Scavenging Capacity (TOSC) units. Uric acid and Trolox were used as the reference antioxidants. Results: The scavenging capacity towards hydroxyl radicals was highest for simvastatin (33756112 U / mg), a value 270.2% higher (P,0.0001) compared to uric acid (reference antioxidant vs. hydroxyl radicals, 1249671 U / mg). Among the tested statins, fluvastatin exhibited the highest anti-peroxyl radical antioxidant capacity (87556187 U / mg) which appeared 50% lower (P,0.0001) compared to Trolox (reference antioxidant vs. peroxyl radicals, 17 4606379 U / mg). Conclusions: All the statins tested have intrinsic antioxidant activity with both anti-hydroxyl and peroxyl radical activity. Simvastatin was the most effective as an anti-hydroxyl radical antioxidant and fluvastatin as an anti-peroxyl radical antioxidant.
Applied Biochemistry and Biotechnology, 2011
Atherosclerosis is a chronic inflammatory disease of multiple etiologies. It is associated with the accumulation of oxidized lipids in arterial lesions leading to coronary heart disease. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (commonly known as statins) are widely used in cardiovascular disease prevention to lower the cholesterol. The antioxidant activity of HMG-CoA reductase inhibitors was studied by lipid peroxidation inhibition assay, DPPH, and hydroxyl radical scavenging-activity methods. The lovastatin (93%) and simvastatin (96%) showed significant action of lipid peroxidation inhibition compared to other HMG-CoA reductase inhibitors. The DPPH radical and hydroxyl radical scavenging activity of simvastatin was 38% and 33%, respectively. The oxidative modification of serum lipid due to reactive oxygen species causes atherosclerosis. This study revealed the importance of lovastatin and simvastatin to prevent oxidative stress-related cardiovascular diseases.
Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo
Biochemical and Biophysical Research Communications, 2006
Heme oxygenase-1 (HO-1) plays a central role in antioxidant and anti-inflammatory actions, which may be mediated through its formation of biliverdin/bilirubin and carbon monoxide. HMG-CoA reductase inhibitors (statins) induce in vitro HO-1 expression and are reported to have pleiotropic benefits that reduce oxidative stress in the vasculature. We characterized the effects of statins on in vivo HO-1 expression in various extravascular tissues: liver, lung, brain, and heart. Adult mice were orally administered simvastatin, lovastatin, atorvastatin, or rosuvastatin. HO activity significantly increased in a statin-and tissue-specific manner, with all statins increasing heart and lung activity within 24 h. Significant elevations of HO-1 protein and mRNA were also observed in heart and lung after atorvastatin treatment. We conclude that in vivo HO-1 induction is statin-and tissue-specific. Through this pathway, statins may confer antioxidant and anti-inflammatory actions in the vasculature and extravascular systems.
Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities
Atherosclerosis, 2004
Low-density lipoprotein (LDL) cholesterol is an established risk factor for coronary heart disease (CHD). In the presence of oxidative stress LDL particles can become oxidized to form a lipoprotein species that is particularly atherogenic. Indeed, oxidized LDL (oxLDL) is pro-inflammatory, it can cause endothelial dysfunction and it readily accumulates within the arterial wall. Several factors may influence the susceptibility of LDL to oxidation, including its size and composition, and the presence of endogenous antioxidant compounds, such as ␣-tocopherol. Individuals with type 2 diabetes or the metabolic syndrome have high levels of oxidative stress and consequently are at an increased risk for cardiovascular events. Reducing oxidative stress has been proposed as a potential approach to prevent CHD and antioxidant vitamins have been employed with encouraging results in experimental models of atherosclerosis. However, clinical trials have not demonstrated consistent beneficial effects of antioxidants on cardiovascular outcomes. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the first-line choice for lowering total and LDL cholesterol levels and they have been proven to reduce the risk of CHD. Recent data suggest that these compounds, in addition to their lipid-lowering ability, can also reduce the production of reactive oxygen species and increase the resistance of LDL to oxidation. It may be that the ability of statins to limit the oxidation of LDL contributes to their effectiveness at preventing atherosclerotic disease. (R.S. Rosenson). may also be at increased risk of developing CHD. Indeed, although levels of LDL may not be elevated, its atherogenic potential may be increased by oxidative modification.