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Is there a role for the macrophage 5-lipoxygenase pathway in aortic aneurysm development in apolipoprotein
Colin D Funk1, Richard Yang Cao, Lei Zhao
1Department of Physiology, Queen's University, Kingston, ON K7L 3N6 Canada. funkc@post.queensu.ca
Abstract:
Activation of the 5-lipoxygenase (5-LO) pathway leads to the biosynthesis of proinflammatory leukotriene (LT) lipid mediators in macrophages, mast cells, and other inflammatory cell types. A recent surge in interest in this pathway within the cardiovascular system has arisen from a variety of exciting findings using genetic, pathological specimen, and biochemical approaches in humans and mice. We found that a subset of CD68-positive macrophages, localized within the adventitial layer of apolipoprotein E (apo E)-deficient mice, expressed 5-LO and that these cells represented a significant cellular component of aortic aneurysms induced by an atherogenic diet containing cholate. Surprisingly, almost no 5-LO-expressing cells were observed in atherosclerotic lesions in the same mice. Correspondingly, lesion size in the fat-fed mice did not depend on 5-LO gene expression but aneurysm incidence was reduced in the absence of the 5-LO pathway. We are currently exploring the potential mechanisms for 5-LO/LT involvement in aneurysm pathogenesis and if this pathway might come into play in other models such as induction by angiotensin II.
Insights
The 5-lipoxygenase (5-LO) pathway is involved in aortic aneurysms, not atherosclerosis, in mice. Inhibiting 5-LO reduced aneurysm incidence, suggesting a therapeutic target for cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Lipid Mediator Synthesis
Background:
- The 5-lipoxygenase (5-LO) pathway produces proinflammatory leukotriene (LT) mediators.
- Recent research highlights the cardiovascular relevance of the 5-LO pathway.
- 5-LO is found in macrophages within the adventitia of apoE-deficient mouse aortas.
Purpose of the Study:
- To investigate the role of 5-LO and its lipid mediators in the pathogenesis of aortic aneurysms.
- To determine if 5-LO expression differs between atherosclerotic lesions and aneurysms.
- To assess the impact of 5-LO deficiency on aneurysm development.
Main Methods:
- Utilized apolipoprotein E (apoE)-deficient mice fed an atherogenic diet.
- Analyzed macrophage (CD68-positive) 5-LO expression in aortic adventitia and atherosclerotic lesions.
- Assessed aneurysm incidence and lesion size in wild-type and 5-LO knockout mice.
Main Results:
- 5-LO was expressed in macrophages within aortic adventitia, a key component of diet-induced aneurysms.
- Minimal 5-LO expression was observed in atherosclerotic lesions.
- Aneurysm incidence was significantly reduced in 5-LO deficient mice, while lesion size was unaffected.
Conclusions:
- The 5-lipoxygenase pathway plays a specific role in aortic aneurysm formation, distinct from its role in atherosclerosis.
- Targeting the 5-LO/leukotriene pathway may offer a novel therapeutic strategy for preventing aortic aneurysms.
- Further research is warranted to elucidate the precise mechanisms of 5-LO/LT involvement in aneurysm pathogenesis.
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