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Dual 12/15- and 5-lipoxygenase deficiency in macrophages alters arachidonic acid metabolism and attenuates peritonitis and atherosclerosis in ApoE knock-out mice.

ABSTRACT: Lipoxygenase (LO) enzymes catalyze the conversion of arachidonic acid (AA) into biologically active lipid mediators. Two members, 12/15-LO and 5-LO, regulate inflammatory responses and have been studied for their roles in atherogenesis. Both 12/15-LO and 5-LO inhibitors have been suggested as potential therapy to limit the development of atherosclerotic lesions. Here we used a genetic strategy to disrupt both 12/15-LO and 5-LO on an apolipoprotein E (apoE) atherosclerosis-susceptible background to study the impact of dual LO blockade in atherosclerosis and inflammation. Resident peritoneal macrophages are the major cell type that expresses both LO enzymes, and we verified their absence in dual LO-deficient mice. Examination of AA conversion by phorbol myristate acetate-primed and A23187-challenged macrophages from dual LO-deficient mice revealed extensive accumulation of AA with virtually no diversion into the most common cyclooxygenase (COX) products measured (prostaglandin E2 and thromboxane B2). Instead the COX-1 by-products 11-hydroxy-eicosatetraenoic acid (HETE) and 15-HETE were elevated. The interrelationship between the two LO pathways in combination with COX-1 inhibition (SC-560) also revealed striking patterns of unique substrate utilization. 5-LO- and dual LO-deficient mice exhibited an attenuated response to zymosan-induced peritoneal inflammation, emphasizing roles for 5-LO in regulating vascular permeability. We observed gender-specific attenuation of atheroma formation at 6 months of age at both the aortic root and throughout the entire aorta in chow-fed female dual LO-deficient mice. We propose that some of the inconsistent data obtained with single LO-deficient mice could be attributable to macrophage-specific patterns of altered AA metabolism.

SUBMITTER: Poeckel D

PROVIDER: S-EPMC2742872 | biostudies-other | 2009 Jul

REPOSITORIES: biostudies-other

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Dual 12/15- and 5-lipoxygenase deficiency in macrophages alters arachidonic acid metabolism and attenuates peritonitis and atherosclerosis in ApoE knock-out mice.

Poeckel Daniel D Zemski Berry Karin A KA Murphy Robert C RC Funk Colin D CD

The Journal of biological chemistry 20090609 31

Lipoxygenase (LO) enzymes catalyze the conversion of arachidonic acid (AA) into biologically active lipid mediators. Two members, 12/15-LO and 5-LO, regulate inflammatory responses and have been studied for their roles in atherogenesis. Both 12/15-LO and 5-LO inhibitors have been suggested as potential therapy to limit the development of atherosclerotic lesions. Here we used a genetic strategy to disrupt both 12/15-LO and 5-LO on an apolipoprotein E (apoE) atherosclerosis-susceptible background ...[more]

PMID: 19509298

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Project description:BACKGROUND:Sodium glucose co-transporter2 inhibitors reduce the incidence of cardiovascular events in patients with type 2 diabetes mellitus based on the results of recent cardiovascular outcome studies. Herein, we investigated the effects of long-term treatment with canagliflozin on biochemical and immunohistochemical markers related to atherosclerosis and atherosclerosis development in the aorta of apolipoprotein E knockout (Apo-E(-/-)) mice. METHODS:At the age of 5 weeks, mice were switched from normal to a high-fat diet. After 5 weeks, Apo-E(-/-) mice were divided into control-group (6 mice) treated with 0.5% hydroxypropyl methylcellulose and Cana-group (7 mice) treated with canagliflozin (10 mg/kg per day) per os. After 5 weeks of intervention, animals were sacrificed, and heart and aorta were removed. Sections stained with hematoxylin-eosin (H&E) were used for histomorphometry whereas Masson's stained tissues were used to quantify the collagen content. Immunohistochemistry to assess MCP-1, CD68, a-smooth muscle actin, MMP-2, MMP-9, TIMP-1 and TIMP-2 expression was carried out and q-PCR experiments were performed to quantify mRNA expression. RESULTS:Canagliflozin-group mice had lower total-cholesterol, triglycerides and glucose levels (P?<?0.01), while heart rate was significantly lower (P?<?0.05). Histomorphometry revealed that one in seven Cana-group mice versus four in six control mice developed atheromatosis, while aortic root plaque was significantly less, and collagen was 1.6 times more intense in canagliflozin-group suggesting increased plaque stability. Immunohistochemistry revealed that MCP-1 was significantly less expressed (P?<?0.05) in the aortic root of canagliflozin-group while reduced expression of a-actin and CD68 was not reaching significance (P?=?0.15). VCAM-1 and MCP-1 mRNA levels were lower (P?=?0.02 and P?=?0.07, respectively), while TIMP-1/MMP-2 ratio expression was higher in canagliflozin-group approaching statistical significance (P?=?0.07). CONCLUSIONS:Canagliflozin attenuates the progression of atherosclerosis, reducing (1) hyperlipidemia and hyperglycemia, and (2) inflammatory process, by lowering the expression of inflammatory molecules such as MCP-1 and VCAM-1. Moreover, canagliflozin was found to increase the atherosclerotic plaque stability via increasing TIMP-1/MMP-2 ratio expression.

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Dataset Information

Dual 12/15- and 5-lipoxygenase deficiency in macrophages alters arachidonic acid metabolism and attenuates peritonitis and atherosclerosis in ApoE knock-out mice.

Publications

Dual 12/15- and 5-lipoxygenase deficiency in macrophages alters arachidonic acid metabolism and attenuates peritonitis and atherosclerosis in ApoE knock-out mice.

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