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  • Review Article
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The potential for novel anti-inflammatory therapies for coronary artery disease

Nature Reviews Drug Discovery volume 1, pages 122–130 (2002)Cite this article

Key Points

  • Although drugs that lead to cholesterol and lipid lowering have proved to have significant effects in lowering cardiovascular morbidity and mortality, coronary artery disease remains a principal cause of death worldwide. So, there is a clear need for the discovery of additional therapeutic approaches to control this disease adequately. In addition to therapies that target novel mechanisms of regulating lipid metabolism, recent data indicate that targeting the inflammatory process in the developing vascular plaques could be beneficial.

  • The recruitment, activation and differentiation of monocytes/macrophages to the sub-endothelial space of the nascent vascular lesion, and their subsequent differentiation to lipid-laden foam cells, is the key inflammatory pathway that leads to the development of advanced, necrotic, unstable plaques. Mouse genetics has been used to evaluate the importance of various pathways that are used in the transport of monocytes and macrophages to vascular lesions.

  • A key step in this process is the secretion of inflammatory cytokines, chemoattractants and other reactive molecules from the vascular endothelium and underlying smooth muscle layer after activation by lipids or lipoproteins. These inflammatory molecules stimulate the endothelium to synthesize adhesion molecules, which results in the selective attraction of activated platelets and monocytes to the activated endothelial surface.

  • Mouse studies indicate that low-affinity interactions of selectins and integrins with their cognate ligands might mediate the initial attraction of these circulating vascular cells to the endothelial layer. These low-affinity interactions lead to a slowing, or rolling, of the cells on the endothelium. High-affinity interactions with activated integrins lead to arrest, or firm adherence, of the cells to the endothelial surface. Current data indicate that the E- and P-selectins, as well as vascular cell adhesion molecule 1 (VCAM-1) and the α4β1-integrin (also known as very late (activation) antigen 4; VLA-4), are responsible for mediating rolling and firm arrest of leukocytes on the endothelial surface. After arrest, monocytes migrate across the endothelium in response to a gradient of chemoattractant. The chemokine MCP-1, through its interaction with the monocyte chemokine (CC) motif receptor 2 (CCR2), seems to have an important role in this process. These data indicate that the antagonism of one or more of these monocyte-transport pathways could be of therapeutic use in atherosclerosis.

  • After recruitment of the monocyte/macrophage to the nascent vascular lesion, these cells differentiate into lipid-laden foam cells. The accumulation of lipoprotein particles is mediated by macrophage scavenger receptors, such as MSR-A. After endocytosis of the lipoprotein particles, free cholesterol is released into the cytoplasm, where it can activate the nuclear receptor LXR, which regulates the expression of several key proteins, including the cholesterol efflux pump ABCA1 (ATP-binding cassette, subfamily A, member 1) and the anti-atherogenic apolipoprotein E. A key regulator of this process is the cholesterol esterification–hydrolysis cycle, which modulates the cytoplasmic levels of free cholesterol. Acyl-coenzyme A cholesterol-acetyltransferase (ACAT) esterifies free cholesterol derived from the diet or from lysosomal hydrolysis of endocytosed lipoproteins, and cytoplasmic neutral cholesterol esterases complete the cycle. ACAT inhibitors, such as Pfizer's Avasimibe, are now in advanced clinical trials for the treatment of coronary artery disease.

  • The macrophage/foam cell actively secretes inflammatory cytokines and other reactive molecules that escalate the inflammatory response and ultimately lead to the development of necrotic lesions that are covered with an unstable fibrous cap and are susceptible to rupture. Macrophage metalloproteinases are important mediators of plaque rupture, as well as the arterial remodelling process that is associated with plaque development.

  • Therapies targeted to the attenuation of cellular recruitment, or to the modification of macrophage/foam cell differentiation, should prove to be useful in the treatment of coronary artery disease.

Abstract

Although drugs that lead to cholesterol and lipid lowering have proved to have significant effects in lowering cardiovascular morbidity and mortality, coronary artery disease remains a principal cause of death worldwide. There is a clear need to discover further therapeutic approaches to control this disease adequately. This review focuses on the mechanisms that have been implicated in the recruitment, activation and differentiation of inflammatory monocytes/macrophages in nascent vascular lesions into lipid-laden foam cells. These mechanisms might provide attractive targets for novel therapies for coronary artery disease.

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Figure 1: Development of vascular-wall lesions.
Figure 2: The macrophage/foam cell and its role in lipid metabolism.

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Acknowledgements

M.A.C. would like to acknowledge helpful discussions with S. Wright, Merck Research Laboratiries, during the preparation of this review.

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Authors and Affiliations

  1. Merck Research Laboratories, PO Box 2000, Rahway, 07065, New Jersey, USA

    Margaret A. Cascieri

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DATABASES

LocusLink

ABCA1

ACAT-1

ACAT-2

Ap2

APOB

APOBEC1

Apobec1

APOE

ApoE

CCR2

CCR5

CD36

CRP

CX3CR1

ICAM-1

Icam-1

IL-1

IL-6

iNos

interferon-γ

LDL receptor

Ldlr

LXRα

Lxrα

LXRβ

Lxrβ

MCP-1

MSR-A

NFκB

PPARα

E-selectin

P-selectin

TNF-α

VCAM-1

Vcam-1

VLA-4

OMIM

multiple sclerosis

Glossary

HYPERLIPIDAEMIA

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

ATHEROSCLEROTIC PLAQUE

A lesion within the intima and media of large- and medium-sized arteries that contains high levels of lipids, lipoproteins, activated macrophages, lipid-enriched foam cells and smooth muscle cells. Advanced lesions can become necrotic, and are covered with a fibrous cap that can rupture and cause catastrophic blockage of coronary arteries.

LOW-DENSITY LIPOPROTEIN (LDL).

A class of lipoprotein that carries cholesterol through the bloodstream. The surface of an LDL particle is a monolayer of phospholipid and unesterified cholesterol. The core is hydrophobic, and is rich in fatty esters of cholesterol. The hydrophobic apoliprotein B is embedded in the membrane.

LEUKOCYTE

A general term used to describe any lymphoid cell. Includes all nucleated blood cells that do not contain haemoglobin.

EXTRACELLULAR MATRIX

A complex, three-dimensional network of very large macromolecules that provides contextual information and an architectural scaffold for cellular adhesion and migration.

MYOCARDIAL INFARCTION

Popularly known as a heart attack, this is the death of part of the heart muscle due to sudden loss of blood supply. Typically, the loss of this supply is caused by the complete blockage of a coronary artery by a blood clot.

ANGIOGRAPHY

An X-ray of arteries and veins that is used to diagnose blockages. A catheter is inserted into the vessel, and a contrast agent is injected so that the vessels will be visible on an X-ray.

LOW-DENSITY LIPOPROTEIN RECEPTOR

An endocytotic hepatic receptor that binds apolipoprotein B, thereby internalizing low-density lipoprotein (LDL), which leads to processing that regulates cholesterol and LDL synthesis. Genetic defects in LDL receptors lead to abnormal serum levels of LDL and hyperlipidaemia.

CHOW DIET

A mouse diet with a relatively low fat and cholesterol content. A typical chow diet may contain 4.5% fat and 0.02% cholesterol by weight, whereas a typical high-fat diet (or Western diet) may contain 21% fat and 0.15% cholesterol by weight.

VERY-LOW-DENSITY LIPOPROTEIN

A smaller lipoprotein particle than LDL, the protein component of which is apolipoprotein E.

INTIMA

The innermost layer of endothelial cells in arteries and veins.

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Cascieri, M. The potential for novel anti-inflammatory therapies for coronary artery disease. Nat Rev Drug Discov 1, 122–130 (2002). https://doi.org/10.1038/nrd723

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