Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension‐induced renal injury in mice

Lee, Craig; Imig, John D.; Edin, Matthew L.; Foley, Julie F.; DeGraff, Laura M.; Bradbury, J. Alyce; Graves, Joan P.; Lih, Fred B.; Clark, James; Myers, Page; Perrow, A. Ligon; Lepp, Adrienne; Kannon, M. Alison; Rønnekleiv, Oline K.; Alkayed, Nabil J.; Falck, John R.; Tomer, Kenneth B.; Zeldin, Darryl C.

doi:10.1096/fj.10-160119

Cited by 127 publications

(151 citation statements)

References 52 publications

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“…The effect of CYP2J2 may involve various mechanisms. Although Ang II clearly elevated blood pressure in this AAA model, and overexpression of CYP2J2 or s-EH inhibitor administration have been reported to lower blood pressure ( 7,8,11 ), it is very unlikely for CYP2J2 overexpression to suppress Ang II-induced AAA. A recent study by Cassis et al ( 20 ) demonstrated that Ang II infusionpromoted AAA formation was independent of increases in blood pressure .…”

Section: Discussionmentioning

confidence: 69%

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

Cai

Zhao

Yan

et al. 2013

Journal of Lipid Research

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Abdominal aortic aneurysms (AAAs) mostly occur in humans over 65 years old ( 1, 2 ). The most dreaded complication of AAA is rupture, and it is the 13th leading cause of death in the United States ( 1 ). At the present time, there is no effi cacious pharmacological therapy, and the surgical treatments carry a high mortality ( 2 ). In the past decades, many studies supported the view that infl ammation played an essential role in the pathogenesis of the disease ( 2-4 ).Cytochrome P450 epoxygenase 2J2 (CYP2J2), which is of human origin and mainly expressed in the cardiovascular system, metabolizes arachidonic acids to epoxyeicosatrienoic acids (EETs) ( 5 ). EETs possess diverse biological functions, and observations reveal that EETs exert protective effects on various cardiovascular diseases, including attenuation of heart injuries and anti-hypertension ( 6-13 ). Recently, Zhang et al. ( 5,14 ) reported that administration of soluble epoxide hydrolase (s-EH) inhibitor, which prevents EET hydration, could prevent angiotensin (Ang) II-induced AAA in mice. However, the underlying mechanisms by which EETs exert the effect and whether increased circulation of EETs by CYP2J2 overexpression could prevent AAA formation remain unknown .EETs are the ligands of peroxisome proliferator-activated receptor (PPAR) ␥ and exert anti-infl ammatory effects ( 15 ). Jones et al. ( 16 ) recently reported that activation of PPAR ␥ byAbstract Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to form epoxyeicosatrienoic acids (EETs), which possess various benefi cial effects on the cardiovascular system. However, whether increasing EETs production by CYP2J2 overexpression in vivo could prevent abdominal aortic aneurysm (AAA) remains unknown. Here we investigated the effects of recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression on angiotensin (Ang) II-induced AAA in apoE-defi cient mice. rAAV-CYP2J2 delivery led to an abundant aortic CYP2J2 expression and increased EETs generation. It was shown that CYP2J2 overexpression attenuated matrix metalloproteinase expression and activity, elastin degradation, and AAA formation, which was associated with reduced aortic infl ammation and macrophage infi ltration. In cultured vascular smooth muscle cells (VSMCs), rAAVmediated CYP2J2 overexpression and EETs markedly suppressed Ang II-induced infl ammatory cytokine expression. Moreover, overexpressed CYP2J2 and EETs inhibited Ang II-induced macrophage migration in a VSMC-macrophage coculture system. We further indicated that these protective effects were mediated by peroxisome proliferatoractivated receptor (PPAR) ␥ activation. Taken together, these results provide evidence that rAAV-mediated CYP2J2 overexpression prevents AAA development which is likely via PPAR ␥ activation and anti-infl ammatory action, suggesting that increasing EETs levels could be considered as a potential strategy to prevent and treat AAA. 25 February 2013. Published, JLR Papers in Press, February 26, 2013 DOI 10.1194 , apoE-defi ci...

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Section: Discussionmentioning

confidence: 69%

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

Cai

Zhao

Yan

et al. 2013

Journal of Lipid Research

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“…To determine whether EET autacoids produced by the endothelium promote tissue growth, we have generated three lines of transgenic mice with high endothelial EET levels: mice with endothelial (Tie2-promoter driven) expression of either human CYP2C8 or human CYP2J2 (Tie2-CYP2C8-Tr and Tie2-CYP2J2-Tr) and mice with global disruption of the gene that encodes sEH (sEH-null) (19). Tie2-CYP2C8-Tr and Tie2-CYP2J2-Tr mice have significantly increased endothelial EETs compared with wild-type (WT) mice, as measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (19,20), and sEH-null mice have significantly increased plasma EETs (21). In contrast, COX-and LOX-derived metabolites are unaffected in these mice (20).…”

Section: Resultsmentioning

confidence: 99%

“…ECs were isolated from WT, Tie2-CYP2J2-Tr, Tie2-CYP2C8-Tr, and Tie2-sEH-Tr mice, and LC-MS/MS analysis was performed as described (19,20,22). All human studies were reviewed and approved by the Institutional Review Board at Lahey Clinic Medical Center.…”

Section: Methodsmentioning

confidence: 99%

Epoxyeicosanoids promote organ and tissue regeneration

Panigrahy

Kalish

Huang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

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“…To determine whether EET autacoids produced by the endothelium promote cancer, we generated three lines of transgenic mice with high endothelial EET levels: mice with endothelial (Tie2 promoterdriven) expression of either human CYP2C8 or human CYP2J2 (Tie2-CYP2C8-Tr, Tie2-CYP2J2-Tr) (15) and mice with global disruption of the gene that encodes sEH (sEH-null) (16). ECs isolated from Tie2-CYP2C8-Tr and Tie2-CYP2J2-Tr mice had significantly increased EET levels compared with ECs isolated from WT mice as measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS) (Supplemental Figure 1B), and sEH-null mice have significantly increased plasma EETs compared with WT mice (17).…”

Section: Endothelium-derived Eets Stimulate Primary Tumor Growthmentioning

confidence: 99%

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Panigrahy¹,

Edin²,

Lee³

et al. 2012

J. Clin. Invest.

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295

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Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.

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Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension‐induced renal injury in mice

Cited by 127 publications

References 52 publications

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

Epoxyeicosanoids promote organ and tissue regeneration

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

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