Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities

doi:10.1016/S0021-9150(03)00239-9

Atherosclerosis

Volume 173, Issue 1, March 2004, Pages 1-12

https://doi.org/10.1016/S0021-9150(03)00239-9 Get rights and content

Abstract

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 α-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.

Introduction

Low-density lipoprotein (LDL) cholesterol has been associated with several pro-atherothrombotic processes, including the development of endothelial dysfunction, inflammation, formation of foam cells, and thrombotic sequelae following unstable plaque rupture in atherosclerotic lesions [1]. The link between LDL cholesterol and the development of coronary heart disease (CHD) is well established and consequently it has been recognized by guidelines, which have recommended target levels for reducing the risk of cardiovascular events [2]. However, the contribution of LDL cholesterol to atherosclerosis is complex and those at risk of CHD do not always have elevated levels of this lipoprotein. Individuals with normal LDL cholesterol levels but high levels of oxidative stress, such as patients with hypertension, type 2 diabetes, renal failure or individuals who smoke [3], [4], [5], 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.

The 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins) are considered first-line therapy for modifying LDL levels and reducing the risk of cardiovascular events [2]. In addition to decreasing LDL cholesterol levels, it is now becoming apparent that statins can also positively influence the oxidative susceptibility, and consequently the atherogenicity, of LDL. The aim of this review is to assess the impact of LDL and oxidative stress on atherogenesis, and to evaluate the clinical relevance of the various effects of statins on these different properties.

Section snippets

The role of oxidized LDL in the promotion of atherosclerosis

Some patient populations, such as individuals who smoke or who have diabetes, are at increased risk of CHD [2], [6], [7], [8], even though their LDL cholesterol levels may not be elevated. These individuals are particularly prone to oxidative stress that can lead to the formation of oxidized LDL (oxLDL) [9]. Indeed, the presence of the metabolic syndrome, an agglomeration of risk factors that increases the risk of CHD, has recently been associated with elevated levels of oxLDL [10].

Oxidatively

Determinants of LDL oxidative susceptibility

There are many factors that influence the susceptibility of LDL to oxidation, including its size and composition, and the presence of endogenous pro- and antioxidant compounds. Methodological considerations have dictated that experiments investigating the susceptibility of LDL to oxidation have been performed in vitro, usually utilizing lipoproteins derived from human volunteers, although animal sources have occasionally been used. While in vitro studies can help to provide possible mechanisms

The metabolic syndrome and diabetes: patients under oxidative stress

It is estimated that approximately 47 million US citizens have the metabolic syndrome [86], a pre-diabetic state of increasing prevalence that places patients at an elevated risk of cardiovascular mortality [87]. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines identify patients with the metabolic syndrome by the presence of at least three of the following five symptoms: blood pressure ≥130/≥85 mmHg, fasting glucose ≥110 mg/dl, abdominal obesity (>102

Addressing the balance of oxidative stress

Reducing the amount of oxLDL may represent a useful approach for preventing atherosclerotic diseases. This may be achieved by: (1) reducing oxidative stress and consequently the oxidation of LDL; (2) reducing LDL levels such that there is less available to be oxidized; or (3) reducing both LDL and oxidative stress.

Conclusions

Oxidatively modified LDL has been implicated in the development of atherosclerosis and it can promote atherosclerosis by inducing inflammation and endothelial dysfunction. These pathways are particularly important in the metabolic syndrome. Clinical trials investigating the ability of antioxidants to reduce the risk of atherosclerotic disease have produced disappointing results and it is unlikely that they will displace the use of statins for preventing cardiovascular disease. Statins have been

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ReviewStatins in atherosclerosis: lipid-lowering agents with antioxidant capabilities

Abstract

Introduction

Section snippets

The role of oxidized LDL in the promotion of atherosclerosis

Determinants of LDL oxidative susceptibility

The metabolic syndrome and diabetes: patients under oxidative stress

Addressing the balance of oxidative stress

Conclusions

Metabolism

Trends Cardiovasc. Med.

J. Am. Coll. Cardiol.

Atherosclerosis

Biochem. Biophys. Res. Commun.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Metabolism

Am. J. Cardiol.

Atherosclerosis

Atherosclerosis

J. Lipid Res.

Metabolism

J. Lipid Res.

J. Biol. Chem.

Metabolism

FEBS Lett.

Trends Cardiovasc. Med.

Arch. Biochem. Biophys.

FEBS Lett.

FEBS Lett.

J. Biol. Chem.

Methods Enzymol.

J. Lipid Res.

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

Atherosclerosis

J. Lipid Res.

J. Lipid Res.

J. Biol. Chem.

Am. J. Clin. Nutr.

Atherosclerosis

Antiatherothrombotic properties of statins: implications for cardiovascular event reduction

J. Am. Med. Assoc.

Oxidative stress in chronic renal failure as a cardiovascular risk factor

Clin. Nephrol.

Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study

Arterioscler. Thromb. Vasc. Biol.

Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the multiple risk factor intervention trial

Diabetes Care

Prevention of coronary heart disease in clinical practice: recommendations of the second joint task force of European and other societies on coronary prevention

Eur. Heart J.

Coronary heart disease risk factors ranked by importance for the individual and community. A 21 year follow-up of 12,000 men and women from The Copenhagen City Heart Study

Eur. Heart J.

Oxidant stress in the vasculature

Curr. Atheroscler. Rep.

The metabolic syndrome is associated with elevated circulating oxidized LDL in the health, aging and body composition cohort

Circulation

Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity

N. Engl. J. Med.

Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man

J. Clin. Invest.

Circulating oxidized LDL is associated with subclinical atherosclerosis development and inflammatory cytokines (AIR Study)

Arterioscler. Thromb. Vasc. Biol.

Circulating oxidized low density lipoprotein levels. A biochemical risk marker for coronary heart disease

Arterioscler. Thromb. Vasc. Biol.

Oxidative modifications of LDL increase its binding to extracelluar matrix from human aortic intima: influence of lesion development, lipoprotein lipase and calcium

J. Pathol.

Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis

Proc. Natl. Acad. Sci. U.S.A.

Review
Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities