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Anti-Inflammatory Effects of Statins: Clinical Evidence and Basic Mechanisms

Key Points

  • Recent evidence has shown that the statins, a class of drugs originally designed to manage cardiovascular disorders by lowering cholesterol might, in part, mediate their protective effects by reducing inflammation. Statin-mediated inhibition of inflammation might affect outcomes in cardiovascular trials independently of the extent of lipid-lowering achieved.

  • The role of inflammation in atherogenesis, combined with the observation that statins show benefit in conditions that are not strongly associated with hyperlipidaemia, led to studies into the additional effects of statins.

  • In the clinic, evidence that statins could have favorable and clinically relevant anti-inflammatory effects independent of lipid lowering is derived from studies of endothelial function, clinical trials of organ transplantation, and clinical trials of myocardial infarction and stroke prevention.

  • Of potential interest is the statin-induced reduction of C-reactive protein (CRP), a marker for inflammation; recent data suggests that the CRP-lowering effect of statins might, in addition to lipid lowering, be relevant for progression of disease.

  • Data from experiments in cell culture and animal models show that statins can induce the cellular accumulation of endothelial nitric oxide synthase; inhibit the expression of adhesion molecules and chemokines that recruit inflammatory cells; inhibit expression of pro-coagulant factors and induce anti-coagulant substances; inhibit proliferation and promote apoptosis of vascular smooth muscle cells; and ameliorate platelet hyper-reactivity.

  • Pathways/factors implicated in the cellular effects of statins include the cholesterol biosynthesis pathway, Ras/Rho, nuclear factor-κB and activator protein-1-mediated pro-inflammatory pathways, and nuclear factors such as peroxisome proliferator-activated receptor and Kruppel-like factor-2.

  • Future studies of the benefits of statins will need to focus on anti-inflammatory targets and will need to take into account interindividual variation to the drugs.

Abstract

Chronic inflammation is a key feature of vascular disease states such as atherosclerosis. Multiple clinical studies have shown that a class of medications termed statins lower cardiovascular morbidity and mortality. Originally developed to lower serum cholesterol, increasing evidence suggests that these medications have potent anti-inflammatory effects that contribute to their beneficial effects in patients. Here, we discuss the clinical and experimental evidence underlying the anti-inflammatory effects of these agents.

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Figure 1: Relative risk of future cardiovascular events among initially healthy women according to baseline levels of lipid and inflammatory biomarkers.
Figure 2: Cumulative rates of recurrent myocardial infarction or cardiovascular death among acute coronary syndrome patients treated with statin therapy.
Figure 3: Cumulative rates of recurrent myocardial infarction or cardiovascular death among acute coronary syndrome patients treated with statins.
Figure 4: Progression and regression of atherosclerosis as measured by intravascular ultrasound among coronary artery disease patients treated with statins.
Figure 5: Schematic diagram detailing the cellular effects of statins.

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Acknowledgements

P.M.R. receives additional support from a National Institute of Health Pharmacogenetics and Risk of Cardiovascular Disease (PARC) grant. M.K.J. is supported by grants from the National Institutes of Health.

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Correspondence to Paul M. Ridker.

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P.M.R. is listed as a co-inventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease, and has also received investigator-initiated research grant support from manufacturers of statin agents.

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DATABASES

Entrez Gene

CRP

eNOS

HMGR

ICAM1

IFNγ

IL-6

IL-8

KLF2

LDLR

LFA1

MAC1

MCP1

NSF

p27Kip1

PAI1

RANTES

sCD40L

Thrombomodulin

tPA

VCAM1

OMIM

Dementia

multiple sclerosis

Osteoporosis

rheumatoid arthritis

Glossary

BALLOON ANGIOPLASTY

A medical procedure in which a balloon-tip catheter is inflated inside an artery to open narrowed or blocked blood vessels of the heart (coronary arteries), stretching the intima and leaving a ragged interior surface after deflation, which triggers a healing response and breaking up of plaque.

STENTING

Usually follows angioplasty; a wire mesh tube is placed in a damaged artery to support the arterial walls and keep them open.

AUTOCRINE

Describing an agent secreted from a cell that acts on the cell in which it is produced.

PARACRINE

Describing an agent secreted from a cell that acts on other cells in the local environment.

ISCHAEMIA

A decrease in the blood supply to a bodily organ or tissue caused by constriction or obstruction of the blood.

HYPERLIPIDAEMIA

An excess of lipids, either triglycerides or cholesterol, in the blood. Lipids circulate as free or esterified entities in lipoprotein particles.

HAEMOSTATIC BALANCE

The balance between coagulation and fibrinolysis, maintained by a dynamic process involving fibrinolytic activators, inhibitors and cellular elements such as platelet cytoskeleton, platelet cytoplasmic granules, and platelet cell surfaces.

CAROTID ENDARTERECTOMY

Procedure in which an artery is opened and a portion of atherosclerotic disease (plaque) is removed.

LIPID RAFT

A cholesterol-rich micro-domain within a cell membrane.

PLATELET HYPER-REACTIVITY

Enhanced platelet aggregation and adhesion activity that can be observed in conditions such as inflammation.

ISOPRENOIDS

A large and diverse class of naturally occurring lipids derived from five-carbon isoprene units formed during cholesterol biosynthesis.

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Jain, M., Ridker, P. Anti-Inflammatory Effects of Statins: Clinical Evidence and Basic Mechanisms. Nat Rev Drug Discov 4, 977–987 (2005). https://doi.org/10.1038/nrd1901

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