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Differential leukotriene constrictor responses in human atherosclerotic coronary arteries
S Allen1, M Dashwood, K Morrison
1Department of Cardiothoracic Surgery, Imperial College of Science, Technology & Medicine, Harefield Hospital, Middlesex, UK.
Insights
Atherosclerosis in human coronary arteries is linked to increased sensitivity to leukotrienes (LTC4 and LTD4). These lipids cause contractions, suggesting a role in coronary artery disease progression.
Area of Science:
- Cardiovascular Biology
- Lipid Mediators
- Atherosclerosis Research
Background:
- Leukotrienes are biologically active lipids impacting cardiac function.
- Their role in coronary artery disease (CAD) requires further investigation.
- Understanding leukotriene formation pathways in coronary arteries is crucial.
Purpose of the Study:
- To compare contractile responses to leukotriene C4 (LTC4) and leukotriene D4 (LTD4) in atherosclerotic vs. nonatherosclerotic human coronary arteries.
- To investigate leukotriene binding activity in these arteries.
- To examine the expression of enzymes involved in leukotriene synthesis.
Main Methods:
- Organ bath studies to assess coronary artery contractility.
- Autoradiography to detect leukotriene receptor binding.
- Immunocytochemistry to identify enzyme expression (5-LO, FLAP, LTA4H).
Main Results:
- Nonatherosclerotic arteries showed no response to LTC4/LTD4.
- Atherosclerotic arteries exhibited concentration-dependent contractions to LTC4 and LTD4.
- Specific [3H]-LTC4 binding was observed in atherosclerotic arteries, particularly in smooth muscle cells and plaque regions.
- Enzymes 5-LO, FLAP, and LTA4H were detected in coronary arteries, co-localizing with macrophages.
Conclusions:
- Atherosclerosis is associated with specific leukotriene receptors in human epicardial coronary arteries.
- These receptors mediate hyperreactivity to LTC4 and LTD4.
- This finding highlights a potential mechanism in the pathogenesis of coronary artery disease.
Background:
Leukotrienes are a class of biologically active lipids that have potent effects on the heart. To assess their role in coronary artery disease, we compared the contractile responses of leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and their binding activity in both atherosclerotic and nonatherosclerotic human coronary arteries. We also studied expression of the enzymes that control their formation to understand how the 5-lipoxygenase (5-LO) pathway is activated in the coronary arteries.
Methods And Results:
The capacity of leukotrienes to affect coronary vessel tone and the influence of atherosclerosis was tested in organ baths. Leukotriene receptors were examined by autoradiography, and antibody binding to the various enzymes responsible for their formation was assessed by use of immunocytochemistry. Nonatherosclerotic coronary artery ring segments were unresponsive to LTC4 and LTD4. In contrast, LTC4 and LTD4 induced concentration-dependent contractions in atherosclerotic coronary arteries. Specific [3H]-LTC4 but not LTD4 binding to atherosclerotic coronary artery was evident, with no evidence of specific binding of [3H]-leukotrienes to nonatherosclerotic coronary artery. High-resolution autoradiography identified specific [3H]-LTC4 binding sites to smooth muscle cell and to regions of intimal proliferation and plaque. Cells showing positive antibody binding to 5-LO, FLAP (5-lipoxygenase activating protein), and leukotriene A4 hydrolase were also present in the coronary arteries and had a similar distribution to macrophages.
Conclusions:
Atherosclerosis is associated with a specific leukotriene receptor(s) capable of inducing hyperreactivity of human epicardial coronary arteries in response to LTC4 and LTD4.