Adipose tissue arachidonic acid content is associated with the expression of 5-lipoxygenase in atherosclerotic plaques

Abstract

BackgroundThe content of arachidonic acid in adipose tissue is positively associated with the risk of myocardial infarction, whereas the content of eicosapentaenoic acid in adipose tissue has been reported to be negatively associated with the risk of myocardial infarction. Both arachidonic acid and eicosapentaenoic acid are substrates for the synthesis of pro-inflammatory leukotrienes and leukotrienes derived from eicosapentaenoic acid are generally much less potent. In this study we hypothesized that a high content of arachidonic acid in adipose tissue would reflect a high formation of arachidonic acid derived leukotrienes and a high expression of 5-lipoxygenase in atherosclerotic plaques. Likewise, we hypothesized that a high content of eicosapentaenoic acid in adipose tissue would reflect a low formation of arachidonic acid derived leukotrienes and a low expression of 5-lipoxygenase in plaques.MethodsIn a cross sectional study we included 45 consecutive subjects undergoing femoral thrombendarterectomy. The expression of 5-lipoxygenase in plaques was assessed by a semi-automated image analysis computer programme after immunohistochemical staining with mono-clonal 5-lipoxygenase antibodies. Leukotriene B4 and cysteinyl leukotriene formation from stimulated femoral artery plaques was quantified using ELISA methods. The fatty acid content of adipose tissue biopsies from the thigh was analyzed using gas chromatography. Associations between variables were assessed by Pearson correlations and were further explored in a multivariable linear regression model adjusting for potential confounders.ResultsA high content of arachidonic acid in adipose tissue was associated with a higher expression of 5-lipoxygenase in plaques (r = 0.32, p = 0.03), but no significant associations with leukotriene B4 (r = 0.22, p = 0.14) and cysteinyl leukotriene (r = −0.11, p = 0.46) formation was seen. No significant associations were found between the content of eicosapentaenoic acid in adipose tissue and 5-lipoxygenase expression or leukotriene formation in plaque.ConclusionsAdipose tissue arachidonic acid contents correlated positively with the expression of 5-lipoxygenase in plaques. This association might represent a causal link between adipose tissue arachidonic acid and the risk of myocardial infarction but confirmatory studies are needed.

Arachidonic acid intake and asthma risk in children and adults: a systematic review of observational studies

“…Our previous study indicated that supplementation with 240 or 720 mg ARA per d did not significantly change plasma prostanoids, which are ARA metabolites produced through pathways other than leukotrienes, although plasma ARA levels increased ( 54 ) . Nielsen et al ( 55 ) reported that adipose tissue ARA was not correlated with either cys-LT formation in plaque or total body cys-LT formation in a cross-sectional study of subjects undergoing femoral thromboendarterectomy. Third, ARA metabolites other than cys-LT may decrease asthma risk.…”

BLTR1 and CD36 Expressing Microvesicles in Atherosclerotic Patients and Healthy Individuals

“…This study included 48 participants (24 male/24 female) with symptomatic peripheral arterial disease undergoing femoral thrombendarterectomy as previously described ( 8 ) and 24 healthy controls (9 male/15 female, age >18 years). Exclusion criteria for the participants with femoral atherosclerosis were allergic asthma or rhinitis, systemic steroid treatment, chronic inflammatory diseases, acute coronary syndrome within the last 30 days, cancer, and inability to give informed consent.…”

“…Analyses of LTs and fatty acids in plaques have previously been described by Nielsen et al ( 8 ). Briefly, for LTB4 quantification, plaques removed during femoral artery thrombendarterectomy were cut into smaller pieces and stimulated with calciumionophore A23187 followed by a solid phase immunoassay ELISA.…”

“…The risk of atherosclerosis has also been associated with the intake of the marine n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the more abundant n-6 PUFAs, linoleic acid and arachidonic acid (AA) ( 8 ). Although pro-inflammatory leukotrienes (LTs) are synthesized from both EPA and AA through the 5-lipoxygenase pathway, LTs derived from EPA are much less potent than LTs derived from AA with the most potent being LTB4 ( 8 ).…”

“…The risk of atherosclerosis has also been associated with the intake of the marine n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the more abundant n-6 PUFAs, linoleic acid and arachidonic acid (AA) ( 8 ). Although pro-inflammatory leukotrienes (LTs) are synthesized from both EPA and AA through the 5-lipoxygenase pathway, LTs derived from EPA are much less potent than LTs derived from AA with the most potent being LTB4 ( 8 ). The pro-inflammatory signals are most likely promoted through the high-affinity receptor BLT1 (BLTR1) and the low-affinity receptor BLTR2 ( 9 ) and especially BLTR1 is suggested to be linked to the development and progression of atherosclerosis as studies have demonstrated that treatment with BLTR1 antagonists reduces atherosclerotic lesions in mice ( 10 ).…”