PMID- 28827330 OWN - NLM STAT- MEDLINE DCOM- 20180525 LR - 20240213 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 114 IP - 36 DP - 2017 Sep 5 TI - Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization. PG - E7545-E7553 LID - 10.1073/pnas.1620898114 [doi] AB - Age-related macular degeneration (AMD) is the most common cause of blindness for individuals age 50 and above in the developed world. Abnormal growth of choroidal blood vessels, or choroidal neovascularization (CNV), is a hallmark of the neovascular (wet) form of advanced AMD and leads to significant vision loss. A growing body of evidence supports a strong link between neovascular disease and inflammation. Metabolites of long-chain polyunsaturated fatty acids derived from the cytochrome P450 (CYP) monooxygenase pathway serve as vital second messengers that regulate a number of hormones and growth factors involved in inflammation and vascular function. Using transgenic mice with altered CYP lipid biosynthetic pathways in a mouse model of laser-induced CNV, we characterized the role of these lipid metabolites in regulating neovascular disease. We discovered that the CYP-derived lipid metabolites epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) are vital in dampening CNV severity. Specifically, overexpression of the monooxygenase CYP2C8 or genetic ablation or inhibition of the soluble epoxide hydrolase (sEH) enzyme led to increased levels of EDP and EEQ with attenuated CNV development. In contrast, when we promoted the degradation of these CYP-derived metabolites by transgenic overexpression of sEH, the protective effect against CNV was lost. We found that these molecules work in part through their ability to regulate the expression of key leukocyte adhesion molecules, on both leukocytes and endothelial cells, thereby mediating leukocyte recruitment. These results suggest that CYP lipid signaling molecules and their regulators are potential therapeutic targets in neovascular diseases. FAU - Hasegawa, Eiichi AU - Hasegawa E AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Inafuku, Saori AU - Inafuku S AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Mulki, Lama AU - Mulki L AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Okunuki, Yoko AU - Okunuki Y AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Yanai, Ryoji AU - Yanai R AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Smith, Kaylee E AU - Smith KE AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Kim, Clifford B AU - Kim CB AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Klokman, Garrett AU - Klokman G AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Bielenberg, Diane R AU - Bielenberg DR AD - Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115. FAU - Puli, Narender AU - Puli N AD - Department of Biochemistry, University of Texas Southwestern, Dallas, TX 75390. FAU - Falck, John R AU - Falck JR AD - Department of Biochemistry, University of Texas Southwestern, Dallas, TX 75390. FAU - Husain, Deeba AU - Husain D AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Miller, Joan W AU - Miller JW AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114. FAU - Edin, Matthew L AU - Edin ML AUID- ORCID: 0000-0002-7042-500X AD - Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. FAU - Zeldin, Darryl C AU - Zeldin DC AD - Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. FAU - Lee, Kin Sing Stephen AU - Lee KSS AD - Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616. FAU - Hammock, Bruce D AU - Hammock BD AUID- ORCID: 0000-0003-1408-8317 AD - Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616; bdhammock@ucdavis.edu kip_connor@meei.harvard.edu. FAU - Schunck, Wolf-Hagen AU - Schunck WH AD - Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. FAU - Connor, Kip M AU - Connor KM AUID- ORCID: 0000-0002-2048-9080 AD - Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114; bdhammock@ucdavis.edu kip_connor@meei.harvard.edu. LA - eng GR - Z01 ES025034/ES/NIEHS NIH HHS/United States GR - Z01 ES025034/ImNIH/Intramural NIH HHS/United States GR - R01 ES002710/ES/NIEHS NIH HHS/United States GR - K99 ES024806/ES/NIEHS NIH HHS/United States GR - P42 ES004699/ES/NIEHS NIH HHS/United States GR - U24 DK097154/DK/NIDDK NIH HHS/United States GR - R01 HL111392/HL/NHLBI NIH HHS/United States GR - R01 EY022084/EY/NEI NIH HHS/United States GR - R00 ES024806/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20170821 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Fatty Acids, Unsaturated) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2C8) RN - EC 3.3.2.- (Epoxide Hydrolases) SB - IM MH - Animals MH - Choroidal Neovascularization/*metabolism MH - Cytochrome P-450 CYP2C8/metabolism MH - Cytochrome P-450 Enzyme System/*metabolism MH - Disease Models, Animal MH - Endothelial Cells/metabolism MH - Epoxide Hydrolases/metabolism MH - Fatty Acids, Unsaturated/metabolism MH - Leukocytes/metabolism MH - Lipid Metabolism/*physiology MH - Macular Degeneration/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Second Messenger Systems/*physiology PMC - PMC5594641 OTO - NOTNLM OT - P450 OT - choroidal neovascularization OT - lipid metabolites OT - omega-3 fatty acids OT - oxylipin COIS- Conflict of interest statement: Massachusetts Eye and Ear Infirmary holds a patent application on anticomplement therapeutics in ocular cell death titled Cyp450 lipid metabolites reduce inflammation and angiogenesis (MEEI WO 2014110261 A1: PCT/US2014/010880) (of which K.M.C. and R.Y. are inventors) and has a pending application of the use of sEH inhibitors in inflammation and angiogenesis (of which K.M.C., E.H., and B.D.H. are inventors). Additionally, Massachusetts Eye and Ear has a proprietary interest in photodynamic therapy for conditions involving unwanted ocular neovascularization and has received financial remuneration related to this technology. J.W.M. receives a share of the same in accordance with institutional guidelines. Max Delbruck Center for Molecular Medicine and University of Texas Southwestern hold a patent family on novel eicosanoid derivatives, also encompassing C21 and its use (WO 2010/081683, PCT/EP2010/000140) (of which W.-H.S., J.R.F., and N.P. are inventors). Max Delbruck Center for Molecular Medicine holds a pending patent application of the use of novel eicosanoid derivatives in indications, associated with inflammation and neovascularization (of which W.-H.S. is inventor). EDAT- 2017/08/23 06:00 MHDA- 2018/05/26 06:00 PMCR- 2018/03/05 CRDT- 2017/08/23 06:00 PHST- 2017/08/23 06:00 [pubmed] PHST- 2018/05/26 06:00 [medline] PHST- 2017/08/23 06:00 [entrez] PHST- 2018/03/05 00:00 [pmc-release] AID - 1620898114 [pii] AID - 201620898 [pii] AID - 10.1073/pnas.1620898114 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7545-E7553. doi: 10.1073/pnas.1620898114. Epub 2017 Aug 21.