Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms (original) (raw)
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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...
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.
Statins and Oxidative Stress During Atherogenesis
European Journal of Cardiovascular Prevention & Rehabilitation, 2003
Oxidised low-density lipoprotein (LDL) is believed to be the most atherogenic form of LDL. However, while a number of experimental data support this concept, the protective role of antioxidants that may prevent LDL oxidation in atherosclerosis is only partially confirmed by studies in man. Observational and epidemiological data as well as randomised trials failed to provide clear-cut indications, because of mixed results on the protective role of antioxidants against cardiovascular diseases. In spite of the lack of a general consensus, recent data reinforce the concept that a regular intake of antioxidants present in food blocks the progression of atherosclerosis and that the reduced ability of LDL to oxidise may represent a good marker to follow the action of antioxidants. Among their properties statins also possess antioxidant activities and the aim of this paper is to review the scientific evidence for such an effect and its possible clinical relevance.
The Open Nutraceuticals Journal, 2010
Background: There is evidence that statins are potent and effective agents with several pleiotropic effects for treatment of coronary artery disease(CAD). Statin may have adverse effects, if given in higher doses and in combinations. Methods: Internet search till 2009 and discussion with colleagues. Results: Statins are wonder drugs influencing wide range of physiological, biochemical,and biological functions.This list appears to be quite large and includes hypolipidemic, vasodilative, antithrombotic, antioxidant, antiinflammatory, antiproliferative, anticoagulant, agiogenic and bone formation inducing functions. Myopathy is the most frequent side effect of statins and in some cases may have a form of severe rhabdomyolysis. Less common adverse effects include hepatotoxicity, peripheral neuropathy, impaired myocardial contractility and autoimmune diseases. Rare manifestations of statin intolerance may be; pulmonary, psychiatric, ophthalmic and amyotropic lateral sclerosis. The risk of these unfavorable effects is largely outweighed by great reduction of cardiovascular events in statin users. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. The mechanisms of statin-related myopathy are unclear. The criteria of diagnosis of myopathy do not bother about the symptoms of patients and oxidative stress, in absence of raised muscle enzymes.Coenzyme Q10 and other antioxidants are not considered in the prophylaxis of statin toxicity. Because one study showed no decrease in CoQ in the muscle in presence of toxicity, although several studies indicate a reduction in serum levels. Conclusion: Statins would be used more commonly in near future due to their cholesterol lowering and antiinflammatory effects. There would be a marked increase in the Number of patients with statin toxicity. Several studies have reported a significant reduction in the serum CoQ in patients receiving statins.Such concern has also been expressed by the International College of Cardiology in their meeting in April 2002 and 2005 and 2009, proposing that coenzyme Q10 and other antioxidants should be considered in the prevention as well as treatment of statin intoxication.
Pleiotropic effects of statins: A boulevard to cardioprotection
Arabian Journal of Chemistry, 2016
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, referred to as ''statins'' have been extensively reported to possess lipid lowering effects by inhibiting the synthesis of cholesterol by liver and thereby increasing hepatic cholesterol uptake and reducing circulating lipid levels. Growing body of evidences have shown that apart from lipid lowering effects, statins possess various pleiotropic effects that include improvement in endothelial dysfunction, increased expression of endothelial nitric oxide synthase (eNOS), enhanced bioavailability of nitric oxide (NO), potent antioxidant potential and anti-inflammatory properties. In relation to cardiovascular pathologies, statins have been shown to inhibit atrial myocardial remodeling, prevent atrial fibrillation, conserve NO production in heart failure, reduce activity of small G-proteins in cardiac hypertrophy and protect the myocardium from lethal ischemia/reperfusion (I/R) injury. The mechanisms underlying the cardioprotective potential include phosphatidyl inositol (PI3)-kinase/Akt/eNOS pathway, subsequent activation of ATP sensitive potassium (K ATP) channels by NO resulting in improved myocardial metabolism, release of endogenous adenosine by increasing the activity of adenosine forming enzyme ecto-5V-nucleotidase, inhibition of reactive oxygen species (ROS) production, decrease in oxidative stress and attenuation of apoptosis. The present review article demonstrates the pleiotropic effects of statins beyond their lipid lowering effects. Moreover, the underlying mechanisms involved in stain-induced cardioprotection have been delineated.
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.
Statins in the treatment of chronic heart failure: Biological and clinical considerations
Cardiovascular Research, 2006
Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an overview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines of evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the importance of additional research specifically in CHF models and patients.
Molecular basis of statin-associated myopathy
Atherosclerosis, 2009
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.
Statins: adverse reactions, oxidative stress and metabolic interactions
Pharmacology & therapeutics, 2018
Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are currently the most effective lipid-lowering drugs, effectively reducing the plasma total cholesterol and low-density lipoprotein, while also decreasing three triacylglycerols and increasing plasma high-density lipoprotein to a certain extent. However, the excessive or long-term use of statins can cause in vitro cytotoxicity, in vivo liver injury, liver necrosis, kidney damage, and myopathy in both human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with statins, and various antioxidants have been evaluated to investigate their protective roles against statin-induced liver, kidney, and muscle toxicities. Widespread attention has been given to statin-induced oxidative stress, with and without the use of other drugs. Much of the information about the mechanism for this reduction comes from cell culture and in experimental animal studies. The primar...