Identification of a leukotriene pathway
as a therapeutic target in treating
sleep apnea-related atherosclerosis
Obstructive sleep apnea is a common condition in which breathing while sleeping is blocked by soft tissue of the throat, decreasing oxygen flow. Left untreated, it can lead to heart disease and stroke. Atherosclerosis has been linked to moderate to severe sleep apnea, as those with the condition show signs of early atherosclerosis, but the connection between the two has remained unclear.
Cytokines are one group of signaling molecules in the body that act as chemical messengers, allowing for communication between cells. Sometimes, when there is too much of a cytokine in one place, damage to the body can occur. Recent studies have shown the cytokine group of leukotrienes are related to both obstructive sleep apnea and atherosclerosis, but the mechanisms linking leukotrienes to either condition had not been adequately investigated.
In a paper in the September issue of the Journal of Lipid Research titled “Leukotriene B4 pathway activation and atherosclerosis in obstructive sleep apnea,” Françoise Stanke-Labesque and colleagues of France’s National Institute of Health and Medical Research, known as INSERM, examined the production of a specific LT, leukotriene B4, in polymorphonuclear neutrophil cells from sleep apnea patients and healthy people.
Leukotriene B4 causes white blood cells to adhere to and cross into endothelial walls, a key step in the development of atherosclerosis; this leukotriene also increases the production of other inflammatory cytokines by transcriptionally activating their related genes.
In the study published in the JLR, the cells obtained from patients with sleep apnea had increased production of leukotriene B4 associated with increased messenger RNA expression of 5-lipoxygenase-activating protein, known as FLAP, which is directly involved in production of leukotriene A4, the unhydrolyzed form of leukotriene B4.
In vitro results indicate that the activation of the leukotriene B4 pathway and increased production of leukotriene B4 induces other proinflammatory cytokines, interleukin-6 and monocyte chemotactic protein-1, both of which are major players in the development of atherosclerosis. Because atherosclerosis is such a complicated disease involving many different lifestyle and hereditary factors, the authors concede that this leukotriene pathway activation may not be the sole mechanism for the vascular remodeling that occurs. Still, the findings from Stanke-Labesque et al. point to this particular leukotriene pathway and FLAP as possible therapeutic targets.
Thematic review series on new ways
of treating cardiovascular disease
by targeting specific lipids and lipoproteins
The September issue of the Journal of Lipid Research features a special section marking the beginning of a new thematic review series that explores new therapeutic targets. Entitled “New Lipid and Lipoprotein Targets for the Treatment of Cardiovascular Diseases,” the series is being coordinated by Associate Editor Stanley L. Hazen of the Cleveland Clinic. Hazen has written an introduction to usher in this first installment of five reviews in this series, which survey topics as varied as bile acid receptors to treat dyslipidemias (abnormal levels of lipids in the blood) as reviewed by Geoffrey Porez et al. of Université Lille Nord de France and the ongoing debate of lecithin:cholesterol acyltransferase in a piece by Sandra Kunnen and Miranda van Eck of Leiden University in the Netherlands. Additional reviews in this series with a clinical focus will follow in future issues.
Mary L. Chang (email@example.com) is managing editor of the Journal of Lipid Research and coordinating journal manager of the journal Molecular & Cellular Proteomics.