Leukotriene Signaling in Cardiovascular Pathophysiology

Leukotrienes are bioactive lipid mediators derived from arachidonic acid through the concerted action of 5-lipoxygenase (5-LO) and its activating protein (FLAP). Two main classes exist: leukotriene B₄ (LTB₄), which chiefly signals via BLT receptors to recruit and activate leukocytes, and cysteinyl leukotrienes (CysLTs: LTC₄, LTD₄, LTE₄), which engage CysLT1 and CysLT2 receptors to modulate vascular tone, permeability and immune cell adhesion. In cardiovascular tissues, leukotriene signalling contributes to endothelial dysfunction, intimal hyperplasia, plaque progression and thrombosis. Upregulation of 5-LO pathway enzymes and CysLT receptors has been observed in atherosclerotic plaques, ischemic myocardium and failing hearts, where CysLT-driven inflammation exacerbates infarct size, maladaptive remodelling and microvascular spasm. Conversely, inhibition of leukotriene synthesis or receptor antagonism has shown promise in attenuating post-infarction fibrosis, preserving ejection fraction and reducing platelet activation in acute coronary syndromes. These insights underscore leukotrienes as central mediators at the intersection of lipid metabolism, vascular inflammation and myocardial injury, and highlight the repurposing of established leukotriene modifiers—originally developed for asthma—as potential adjuncts in cardiovascular therapy.

Research from Nature Portfolio

Recent preclinical work in a murine model of myocardial infarction demonstrated that treatment with a selective CysLT1 receptor antagonist markedly reduced expression of pro-inflammatory cytokines, limited infarct expansion and prevented maladaptive ventricular remodelling. Treated animals exhibited smaller infarct scars, reduced left ventricular mass and improved global and regional contractile performance. These findings support the potential for repurposing cysteinyl leukotriene blockade to preserve cardiac structure and function after ischaemic injury.

Leukotriene Signaling in Cardiovascular Pathophysiology publication trend

The graph below shows the total number of articles in leukotriene signaling in cardiovascular pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Cysteinyl leukotrienes (CysLTs): Potent lipid inflammatory mediators (LTC₄, LTD₄, LTE₄) formed via 5-lipoxygenase and FLAP, acting on CysLT1/CysLT2 receptors to regulate vascular permeability and immune cell recruitment.

5-Lipoxygenase (5-LO): Key enzyme that oxygenates arachidonic acid to produce leukotriene A₄, the precursor of both LTB₄ and CysLTs.

CysLT1 receptor: G protein–coupled receptor for cysteinyl leukotrienes, mediating pro-inflammatory and vasoactive responses in endothelial cells and smooth muscle.

FLAP (5-Lipoxygenase-activating protein): Membrane protein essential for delivering arachidonic acid to 5-lipoxygenase and facilitating leukotriene biosynthesis.

Myocardial remodelling: Structural and functional changes in the heart post-injury, including fibrosis, hypertrophy and chamber dilation, which influence long-term cardiac performance.

References

1. Arachidonic Acid Metabolites in Cardiovascular and Metabolic Diseases. International Journal of Molecular Sciences (2018).
2. Role of the Cysteinyl Leukotrienes in the Pathogenesis and Progression of Cardiovascular Diseases. Mediators of Inflammation (2017).
3. Montelukast, an available and safe anti-asthmatic drug, prevents maladaptive remodelling and maintains cardiac functionality following myocardial infarction. Scientific Reports (2024).
4. Montelukast and Acute Coronary Syndrome: The Endowed Drug. Pharmaceuticals (2022).
5. Molecular Pharmacology of Inflammation Resolution in Atherosclerosis. International Journal of Molecular Sciences (2022).
6. Montelukast Use Decreases Cardiovascular Events in Asthmatics. Frontiers in Pharmacology (2021).