Arachidonic acid metabolites in the cardiovascular system: the role of lipoxygenase isoforms in atherogenesis with particular emphasis on vascular remodeling (original) (raw)
Related papers
Clarification of Arachidonic Acid Metabolic Pathway Intricacies
ACS Omega, 2021
Surrounding inflammation activates phospholipase A 2 , which cleaves and releases arachidonic acid (ARA) from cell membranes. The four cis double bonds are instrumental in ARA susceptibility to oxidation, resulting in the generation of numerous bioactive metabolites of critical importance for the immune system, namely inflammation in response to pathogens, resolution of inflammation, wound healing, and mood and energy balance. The ARA metabolism steps are replete with intricacies, deterring researchers from identifying targets, which could be useful in modulating the synthesis of ARA metabolites toward exclusive protection of the host from pathogens, endogenous excessive danger signals, pain, inflammation, stress, and anxiety disorders. While ARA metabolic pathways are reasonably defined, it was deemed mandatory to fully clarify the flow and direction of protons, electrons, and oxygen atoms and the intricacies behind formation and breakage of double bonds and cyclic structures. This in-depth novel information will perfect the development of strategies and drugs aimed at counteracting inflammation and promoting healing.
2013
Background: The 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. Methods: In 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 B 4 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. Results: A 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 B 4 (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. Conclusions: Adipose 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.
Effects of Arachidonic Acid and Its Metabolites on Functional Beta-Cell Mass
Metabolites
Arachidonic acid (AA) is a polyunsaturated 20-carbon fatty acid present in phospholipids in the plasma membrane. The three primary pathways by which AA is metabolized are mediated by cyclooxygenase (COX) enzymes, lipoxygenase (LOX) enzymes, and cytochrome P450 (CYP) enzymes. These three pathways produce eicosanoids, lipid signaling molecules that play roles in biological processes such as inflammation, pain, and immune function. Eicosanoids have been demonstrated to play a role in inflammatory, renal, and cardiovascular diseases as well type 1 and type 2 diabetes. Alterations in AA release or AA concentrations have been shown to affect insulin secretion from the pancreatic beta cell, leading to interest in the role of AA and its metabolites in the regulation of beta-cell function and maintenance of beta-cell mass. In this review, we discuss the metabolism of AA by COX, LOX, and CYP, the roles of these enzymes and their metabolites in beta-cell mass and function, and the possibility ...
Arachidonic acid: Physiological roles and potential health benefits – A review
Journal of Advanced Research, 2018
It is time to shift the arachidonic acid (ARA) paradigm from a harm-generating molecule to its status of polyunsaturated fatty acid essential for normal health. ARA is an integral constituent of biological cell membrane, conferring it with fluidity and flexibility, so necessary for the function of all cells, especially in nervous system, skeletal muscle, and immune system. Arachidonic acid is obtained from food or by desaturation and chain elongation of the plant-rich essential fatty acid, linoleic acid. Free ARA modulates the function of ion channels, several receptors and enzymes, via activation as well as inhibition. That explains its fundamental role in the proper function of the brain and muscles and its protective potential against Schistosoma mansoni and S. haematobium infection and tumor initiation, development, and metastasis. Arachidonic acid in cell membranes undergoes reacylation/deacylation cycles, which keep the concentration of free ARA in cells at a very low level and limit ARA availability to oxidation. Metabolites derived from ARA oxidation do not initiate but contribute to inflammation and most importantly lead to the generation of mediators responsible for resolving inflammation and wound healing. Endocannabinoids are oxidation-independent ARA derivatives, critically important for brain reward signaling, motivational processes, emotion, stress responses, pain, and energy balance. Free ARA and metabolites promote and modulate type 2 immune responses, which are critically important in resistance to parasites and allergens insult, directly via action on eosinophils, basophils, and mast cells and
PLoS ONE, 2012
Inflammation in the vascular wall is important for development of atherosclerosis. We have shown previously that arachidonate 15-lipoxygenase type B (ALOX15B) is more highly expressed in human atherosclerotic lesions than in healthy arteries. This enzyme oxidizes fatty acids to substances that promote local inflammation and is expressed in lipid-loaded macrophages (foam cells) present in the atherosclerotic lesions. Here, we investigated the role of ALOX15B in foam cell formation in human primary macrophages and found that silencing of human ALOX15B decreased cellular lipid accumulation as well as proinflammatory cytokine secretion from macrophages. To investigate the role of ALOX15B in promoting the development of atherosclerosis in vivo, we used lentiviral shRNA silencing and bone marrow transplantation to knockdown mouse Alox15b gene expression in LDL-receptor-deficient (Ldlr 2/2) mice. Knockdown of mouse Alox15b in vivo decreased plaque lipid content and markers of inflammation. In summary, we have shown that ALOX15B influences progression of atherosclerosis, indicating that this enzyme has an active proatherogenic role.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2006
As childhood obesity is increasing, its affects on the cardiovascular system remain unclear. Cyclooxygenase (COX) enzymes metabolize arachidonic acid (AA) into vasoactive prostanoids and their expression is altered in hypertensive animal models. We hypothesized that there would be augmented vasoconstriction to AA, mediated via COX 1 in rats fed a high-fat (HF)-diet for 10 weeks (from 3 to 13 weeks old) compared to those fed regular rat chow. AA induced vasoconstriction was augmented in the aorta from rats fed a HF-diet compared to control. Inhibitors to AA metabolism suggest that COX 1 activity predominates in rats fed a HF-diet. Western blot analysis showed that COX 1 but not COX 2 protein expression was increased in aortic rings stimulated with AA from the rats fed the HF-diet. These results suggest that vasoconstriction induced by AA is augmented in rats fed the HF-diet due to increased COX 1 expression and activity.