title: Intimal smooth muscle cells are a source but not a sensor of anti-inflammatory CYP450 derived oxylipins.
abstract: 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 sEH 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.
authors.affiliation: Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Thomson
authors.affiliation: Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Davies
authors.affiliation: Barts and the London, Queen Mary University, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Yaqoob
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davies, CA 95616-8584, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: University College London, University Street, London, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Gilroy
authors.affiliation: Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK. Electronic address: dbishopbailey@rvc.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
mesh_terms: D000818:Animals; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D054883:Oxylipins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012377:Rodentia; D013552:Swine; D017539:Tunica Intima / Q000166:cytology* / Q000378:metabolism
chemical_list: D054883:Oxylipins; D003577:Cytochrome P-450 Enzyme System
keywords: Epoxygenase; LPS; Oxylipin; Smooth muscle cell; Soluble epoxide hydrolase