Arachidonic Acid Metabolism as a Potential Mediator of Cardiac Fibrosis Associated with Inflammation

Levick, Scott P.; Loch, D. S.; Taylor, Stephen M.; Janicki, Joseph S.

doi:10.4049/jimmunol.178.2.641

Cited by 101 publications

(75 citation statements)

References 84 publications

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“…The effects of arachidonic acid metabolism by cyclooxygenases in heart failure and tissue remodeling have been somewhat controversial with dimorphic effects on remodeling (27). Based on the observations herein, this may very well be due to underlying hormonal modulation by estrogen.…”

Section: Discussionmentioning

confidence: 79%

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Estrogenic modulation of inflammation-related genes in male rats following volume overload

McLarty

Meléndez

Levick

et al. 2012

Physiological Genomics

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Our laboratory has previously reported significant increases of the proinflammatory cytokine TNF-␣ in male hearts secondary to sustained volume overload. These elevated levels of TNF-␣ are accompanied by left ventricular (LV) dilatation and cardiac dysfunction. In contrast, estrogen has been shown to protect against this adverse cardiac remodeling in both female and male rats. The purpose of this study was to determine whether estrogen has an effect on inflammation-related genes that contribute to this estrogen-mediated cardioprotection. Myocardial volume overload was induced by aortocaval fistula in 8 wk old male Sprague-Dawley rats (n ϭ 30), and genes of interest were identified using an inflammatory PCR array in Sham, Fistula, and Fistula ϩ Estrogen-treated (0.02 mg/kg per day beginning 2 wk prior to fistula) groups. A total of 55 inflammatory genes were modified (Ն2-fold change) at 3 days postfistula. The number of inflammatory gene was reduced to 21 genes by estrogen treatment, whereas 13 genes were comparably modulated in both fistula groups. The most notable were TNF-␣, which was downregulated by estrogen, and the TNF-␣ receptors, which were differentially regulated by estrogen. Specific genes related to arachidonic acid metabolism were downregulated by estrogen, including cyclooxygenase-1 and -2. Finally, gene expression for the ␤1-integrin cell adhesion subunit was significantly upregulated in the LV of estrogen-treated animals. Protein levels reflected the changes observed at the gene level. These data suggest that estrogen provides its cardioprotective effects, at least in part, via genomic modulation of numerous inflammation-related genes. aortocaval fistula; tumor necrosis factor-␣; tumor necrosis factor-␣ receptors; prostaglandin; ␤1-integrin THE ABDOMINAL AORTOCAVAL FISTULA model of volume overload is an excellent approach in which to study sex differences in heart failure. In this model, males undergo collagen degradation and develop significant left ventricular (LV) wall thinning, ventricular dilatation, and increased myocardial compliance (5,9,10

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Section: Discussionmentioning

confidence: 79%

“…COX enzymes serve as the initial step in the prostanoid pathway (27), and changes in arachidonic acid metabolism likely influence myocardial remodeling. The mRNA levels of COX-1 and COX-2 were significantly increased in the Fistula group compared with the Fistula ϩ Estrogen group (Fig.…”

Section: Estrogen Modulation Of Cox Mrna Protein and Metabolite Levmentioning

confidence: 99%

Estrogenic modulation of inflammation-related genes in male rats following volume overload

McLarty

Meléndez

Levick

et al. 2012

Physiological Genomics

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“…AA is one of the most tightly regulated fatty acids in cell membrane phospholipids as it affects the way cells behave, and its actions have far-ranging effects (85,89) . Diets high in LA or AA could potentially result in overactivity of AA-derived eicosanoids which could lead to an overactive immune system which has been hypothesised to cause damage to host tissues, lead to the formation of thrombi, and facilitate inflammatory disorders (90)(91)(92)(93) . Despite the proinflammatory effects of AA-derived eicosanoids, it is now recognised that not all the metabolites from AA act in the same manner and some metabolites are shown to promote bronchodilation in normal subjects (94) but may cause constriction in patients with asthma because of activation of reflex cholinergic bronchoconstriction (95,96) .…”

Section: Nutrition Research Reviewsmentioning

confidence: 99%

n-3 Fatty acids and asthma

2016

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Asthma is one of the most common and prevalent problems worldwide affecting over 300 million individuals. There is some evidence from observational and intervention studies to suggest a beneficial effect of n-3 PUFA in inflammatory diseases, specifically asthma. Marine-based n-3 PUFA have therefore been proposed as a possible complementary/alternative therapy for asthma. The proposed anti-inflammatory effects of n-3 fatty acids may be linked to a change in cell membrane composition. This altered membrane composition following n-3 fatty acid supplementation (primarily EPA and DHA) can modify lipid mediator generation via the production of eicosanoids with a reduced inflammatory potential/impact. A recently identified group of lipid mediators derived from EPA including E-series resolvins are proposed to be important in the resolution of inflammation. Reduced inflammation attenuates the severity of asthma including symptoms (dyspnoea) and exerts a bronchodilatory effect. There have been no major health side effects reported with the dietary supplementation of n-3 fatty acids or their mediators; consequently supplementing with n-3 fatty acids is an attractive non-pharmacological intervention which may benefit asthma.

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“…The cell damage associated with inflammation causes cell membranes to release arachidonic acid (Levick et al, 2007). Arachidonic acid undergoes two metabolic pathways: the cyclooxygenase (COX) pathway involving cyclooxgenase-1 (COX-1) and cyclooxgenase-2 (COX-2) to produce the prostaglandins and thromboxanes (Rainsford, 2007); and the lipoxygenase (LOX) pathway, involving 5-lipoxygenase (5-LOX), 12-lipoxygenase (12-LOX) and , to produce the leukotrienes and hydroperoxy fatty acids (Samuelsson et al, 1987;Yedgar et al, 2007).…”

Section: Introductionmentioning

confidence: 99%