Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization

Eiichi Hasegawa, Saori Inafuku, Lama Mulki, Yoko Okunuki, Ryoji Yanai, Kaylee E. Smith, Clifford B. Kim, Garrett Klokman, Diane R. Bielenberg, Narender Puli, John R. Falck, Deeba Husain, Joan W. Miller, Matthew L. Edin, Darryl C. Zeldin, Kin Sing Stephen Lee, Bruce D. Hammock, Wolf Hagen Schunck, Kip M. Connor

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E7545-E7553
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number36
DOIs
StatePublished - Sep 5 2017

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Choroidal Neovascularization
Second Messenger Systems
Mixed Function Oxygenases
Cytochrome P-450 Enzyme System
Lipids
Epoxide Hydrolases
Macular Degeneration
Blood Vessels
Leukocytes
Inflammation
Acids
Aptitude
Biosynthetic Pathways
Cell Adhesion Molecules
Blindness
Unsaturated Fatty Acids
Transgenic Mice
Intercellular Signaling Peptides and Proteins
Lasers
Endothelial Cells

Keywords

  • Choroidal neovascularization
  • Lipid metabolites
  • Omega-3 fatty acids
  • Oxylipin
  • P450

ASJC Scopus subject areas

  • General

Cite this

Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization. / Hasegawa, Eiichi; Inafuku, Saori; Mulki, Lama; Okunuki, Yoko; Yanai, Ryoji; Smith, Kaylee E.; Kim, Clifford B.; Klokman, Garrett; Bielenberg, Diane R.; Puli, Narender; Falck, John R.; Husain, Deeba; Miller, Joan W.; Edin, Matthew L.; Zeldin, Darryl C.; Lee, Kin Sing Stephen; Hammock, Bruce D.; Schunck, Wolf Hagen; Connor, Kip M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 36, 05.09.2017, p. E7545-E7553.

Research output: Contribution to journalArticle

Hasegawa, E, Inafuku, S, Mulki, L, Okunuki, Y, Yanai, R, Smith, KE, Kim, CB, Klokman, G, Bielenberg, DR, Puli, N, Falck, JR, Husain, D, Miller, JW, Edin, ML, Zeldin, DC, Lee, KSS, Hammock, BD, Schunck, WH & Connor, KM 2017, 'Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 36, pp. E7545-E7553. https://doi.org/10.1073/pnas.1620898114
Hasegawa, Eiichi ; Inafuku, Saori ; Mulki, Lama ; Okunuki, Yoko ; Yanai, Ryoji ; Smith, Kaylee E. ; Kim, Clifford B. ; Klokman, Garrett ; Bielenberg, Diane R. ; Puli, Narender ; Falck, John R. ; Husain, Deeba ; Miller, Joan W. ; Edin, Matthew L. ; Zeldin, Darryl C. ; Lee, Kin Sing Stephen ; Hammock, Bruce D. ; Schunck, Wolf Hagen ; Connor, Kip M. / Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 36. pp. E7545-E7553.
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abstract = "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.",
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AU - Hasegawa, Eiichi

AU - Inafuku, Saori

AU - Mulki, Lama

AU - Okunuki, Yoko

AU - Yanai, Ryoji

AU - Smith, Kaylee E.

AU - Kim, Clifford B.

AU - Klokman, Garrett

AU - Bielenberg, Diane R.

AU - Puli, Narender

AU - Falck, John R.

AU - Husain, Deeba

AU - Miller, Joan W.

AU - Edin, Matthew L.

AU - Zeldin, Darryl C.

AU - Lee, Kin Sing Stephen

AU - Hammock, Bruce D.

AU - Schunck, Wolf Hagen

AU - Connor, Kip M.

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N2 - 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.

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