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  • Review Article
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Leukotriene modifiers as potential therapeutics for cardiovascular disease

Nature Reviews Drug Discovery volume 4, pages 664–672 (2005)Cite this article

Key Points

  • 5-Lipoxygenase (5-LO) catalyses the formation of leukotrienes from arachidonic acid in inflammatory cells.

  • Leukotriene B4 is a potent neutrophil chemoattractant and the cysteinyl leukotrienes are mediators of vascular permeability, bronchoconstriction and anaphylactic reactions. They bind to BLT1/BLT2 and CysLT1/CysLT2 receptors, respectively.

  • Leukotrienes have been a prime target in asthma and drugs were developed — known as leukotriene modifiers — that block airway inflammation and bronchoconstriction. The drugs that are currently used block 5-LO and the CysLT1 receptor.

  • Recently, much attention has turned towards the potential roles of the 5-LO pathway in promoting inflammation in cardiovascular disease, including atherosclerosis and aortic aneurysms from both human and mouse studies.

  • The precise functions of the leukotrienes in cardiovascular disease are being evaluated and based on genetic studies a clinical trial has been initiated to evaluate the efficacy of a 5-LO-activating protein inhibitor in the secondary prevention of myocardial infarction.

Abstract

Owing to their anti-inflammatory properties, leukotriene modifiers have been the primary therapeutics in asthma management for several years. Although blocking the inflammatory component of human disease is a long-standing and established concept, the use of leukotriene modifiers in treating the inflammatory component of cardiovascular disease encompassing atherosclerosis, myocardial infarction, stroke and aortic aneurysm has, surprisingly, only been seriously contemplated in the past few years. As reviewed here, several exciting studies have recently contributed to this expanding area of interest, and so far one leukotriene modifier has entered Phase II clinical trials to assess its potential for reducing the risk of heart attacks.

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Figure 1: Leukotriene biosynthetic cascade.
Figure 2: Various members of the three classes of leukotriene-modifier drugs.
Figure 3: Genetic variants in the 5-lipoxygenase/leukotriene pathway.
Figure 4: Model for 5-lipoxygenase/leukotriene pathway involvement in aortic aneurysm and adventitial inflammation pathogenesis.

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Acknowledgements

C.D.F. holds a Canada Research Chair in Molecular, Cellular and Physiological Medicine. Supported by funds from the Canadian Institutes of Health Research, National Institutes of Health, Canadian Foundation for Innovation and Ontario Innovation Trust. I gratefully acknowledge discussions with L. Zhao, A. Habenicht and J. Evans over the course of our studies examining 5-lipoxygenase and cardiovascular disease. I regret the likely oversight of some relevant references from my colleagues due to page constraints.

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  1. Departments of Biochemistry and Physiology, Queen's University, Kingston, K7L 3N6, ON, Canada

    Colin D. Funk

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C.D.F. receives research funding from Merck & Co. and consulting fees from Critical Therapeutics Inc.

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DATABASES

Entrez Gene

ALOX5

ALOX5AP

BLT1

BLT2

CRP

CysLT1

CysLT2

IL-6

IL-8

MPO

OMIM

Arthritis

Inflammatory bowel disease

Psoriasis

FURTHER INFORMATION

decode Genetics

Glossary

G-PROTEIN-COUPLED RECEPTORS

G-protein-coupled receptors comprise the largest gene family of receptors and mediate a broad array of signalling to peptides, lipids, amines and a variety of hormones.

HPETE

The initial product of the 5-lipoxygenase pathway is a hydroperoxyeicosatetraenoic acid, literally an oxygenated arachidonic acid molecule.

ASTHMA EARLY AND LATE PHASE AIRWAY RESPONSE

An immune system disorder characterized by a rapid fall in lung function to allergen exposure/exercise (early-phase response), followed several hours later by a second, delayed fall (late-phase airway resposne).

SP1

A member of a family of transcription factors that bind preferentially to promoter regions of genes containing GC-rich sequences.

ω3 POLYUNSATURATED FATTY ACID

Important dietary lipid characterized by one of the double bonds situated 3 carbons from the 'omega' end of the carbon chain backbone derived most often from marine sources.

ω6 POLYUNSATURATED FATTY ACID

Important dietary lipid characterized by one of the double bonds situated 6 carbons from the 'omega' end of the carbon chain backbone derived most often from animal sources.

APOE

Apolipoprotein E is a key protein constituent of certain lipoproteins and a ligand for hepatic receptors. Deficiency of this protein in mice leads to increased plasma cholesterol and atherosclerosis.

LDL-R

The low-density lipoprotein receptor is the main portal of cholesterol entry into cells. Most cells are capable of synthesizing LDL via the mevalonate pathway. Deficiency of this receptor in mice leads to atherosclerosis on a high-fat diet.

ABDOMINAL AORTIC ANEURYSM

A chronic degenerative and remodelling process of a specific region of the arterial wall that is characterized by dilation greater than 3.0 cm in humans.

QRT-PCR

Quantitative real-time polymerase chain reaction is the current state-of-the-art method for assessing gene expression.

LC/MS/MS

Liquid chromatography/mass spectrometry/mass spectrometry is a robust method for the analytical measurement and precise identification of biological and chemical metabolites.

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Funk, C. Leukotriene modifiers as potential therapeutics for cardiovascular disease. Nat Rev Drug Discov 4, 664–672 (2005). https://doi.org/10.1038/nrd1796

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