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Title: Intimal smooth muscle cells are a source but not a sensor of anti-inflammatory CYP450 derived oxylipins

Vascular pathologies are associated with changes in the presence and expression of morphologically distinct vascular smooth muscle cells. In particular, in complex human vascular lesions and models of disease in pigs and rodents, an intimal smooth muscle cell (iSMC) which exhibits a stable epithelioid or rhomboid phenotype in culture is often found to be present in high numbers, and may represent the reemergence of a distinct developmental vascular smooth muscle cell phenotype. The CYP450-oxylipin - soluble epoxide hydrolase (sEH) pathway is currently of great interest in targeting for cardiovascular disease. sEH inhibitors limit the development of hypertension, diabetes, atherosclerosis and aneurysm formation in animal models. We have investigated the expression of CYP450-oxylipin-sEH pathway enzymes and their metabolites in paired intimal (iSMC) and medial (mSMC) cells isolated from rat aorta. iSMC basally released significantly larger amounts of epoxy-oxylipin CYP450 products from eicosapentaenoic acid > docosahexaenoic acid > arachidonic acid > linoleic acid, and expressed higher levels of CYP2C12, CYP2B1, but not CYP2J mRNA compared to mSMC. When stimulated with the pro-inflammatory TLR4 ligand LPS, epoxy-oxylipin production did not change greatly in iSMC. In contrast, LPS induced epoxy-oxylipin products in mSMC and induced CYP2J4. iSMC and mSMC express sEH which metabolizes primary epoxy-oxylipins to their dihydroxy-counterparts. The sEHmore » inhibitors TPPU or AUDA inhibited LPS-induced NFκB activation and iNOS induction in mSMC, but had no effect on NFκB nuclear localization or inducible nitric oxide synthase in iSMC; effects which were recapitulated in part by addition of authentic epoxy-oxylipins. iSMCs are a rich source but not a sensor of anti-inflammatory epoxy-oxylipins. Complex lesions that contain high levels of iSMCs may be more resistant to the protective effects of sEH inhibitors. - Highlights: • We examined oxylipin production in different SMC phenotypes. • Intimal SMC produced more oxylipins than medial SMC. • CYPs were differentially expressed and regulated by LPS in intimal and medial SMC. • sEH inhibitors reduce inflammation in medial but not intimal SMC. • Intimal SMC are a source but not sensor of epoxy-oxylipins.« less
Authors:
 [1] ; ;  [2] ;  [1] ;  [3] ;  [4] ;  [5] ;  [2] ;  [1]
  1. Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU (United Kingdom)
  2. Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC 27709 (United States)
  3. Barts and the London, Queen Mary University, Charterhouse Square, London EC1M 6BQ (United Kingdom)
  4. Department of Entomology and Comprehensive Cancer Center, University of California, Davies, CA 95616-8584 (United States)
  5. University College London, University Street, London (United Kingdom)
Publication Date:
OSTI Identifier:
22462146
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 463; Journal Issue: 4; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AORTA; ARACHIDONIC ACID; ARTERIOSCLEROSIS; ENZYMES; EPOXIDES; HYPERTENSION; INFLAMMATION; LINOLEIC ACID; MESSENGER-RNA; METABOLITES; MUSCLES; NITRIC OXIDE; PATHOLOGY; PHENOTYPE; RATS; RECEPTORS; SENSORS; SWINE