Epoxyeicosatrienoic acids protect rat hearts against tumor necrosis factor-α-induced injury

Epoxyeicosatrienoic acids (EET), the primary arachidonic acid metabolites of cytochrome P450 2J (CYP2J) epoxygenases, possess potent vasodilatory, anti-inflammatory, antiapoptotic, and mitogenic effects. To date, little is known about the role of CYP2J2 and EETs in tumor necrosis factor (TNF)-α–induced cardiac injury. We utilized cell culture and in vivo models to examine the effects of exogenously applied EETs or CYP2J2 overexpression on TNF-α–induced cardiac apoptosis and cardiac dysfunction. In neonatal rat cardiomyocytes, TNF-α–induced apoptosis was markedly attenuated by EETs or CYP2J2 overexpression, leading to significantly improved cell survival. Further studies showed that TNF-α decreased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL, decreased IκBα and PPARγ, and also inhibited PI3K-dependent Akt and EGFR signaling. Both EETs and CYP2J2 overexpression reversed the effects of TNF-α on these pathways. Furthermore, overexpression of CYP2J2 in rats prevented the decline in cardiac function that is normally observed in TNF-α-challenged animals. These results demonstrate that EETs or CYP2J2 overexpression can prevent TNF-α–induced cardiac cell injury and cardiac dysfunction by inhibiting apoptosis, reducing inflammation, and enhancing PPARγ expression. Targeting the CYP2J2 epoxygenase pathway may represent a novel approach to mitigate cardiac injury in diseases such as heart failure, where increased TNF-α levels are known to occur. Epoxyeicosatrienoic acids (EET), the primary arachidonic acid metabolites of cytochrome P450 2J (CYP2J) epoxygenases, possess potent vasodilatory, anti-inflammatory, antiapoptotic, and mitogenic effects. To date, little is known about the role of CYP2J2 and EETs in tumor necrosis factor (TNF)-α–induced cardiac injury. We utilized cell culture and in vivo models to examine the effects of exogenously applied EETs or CYP2J2 overexpression on TNF-α–induced cardiac apoptosis and cardiac dysfunction. In neonatal rat cardiomyocytes, TNF-α–induced apoptosis was markedly attenuated by EETs or CYP2J2 overexpression, leading to significantly improved cell survival. Further studies showed that TNF-α decreased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL, decreased IκBα and PPARγ, and also inhibited PI3K-dependent Akt and EGFR signaling. Both EETs and CYP2J2 overexpression reversed the effects of TNF-α on these pathways. Furthermore, overexpression of CYP2J2 in rats prevented the decline in cardiac function that is normally observed in TNF-α-challenged animals. These results demonstrate that EETs or CYP2J2 overexpression can prevent TNF-α–induced cardiac cell injury and cardiac dysfunction by inhibiting apoptosis, reducing inflammation, and enhancing PPARγ expression. Targeting the CYP2J2 epoxygenase pathway may represent a novel approach to mitigate cardiac injury in diseases such as heart failure, where increased TNF-α levels are known to occur. Cytochrome P450 epoxygenases of the 2J subfamily (CYP2J) are abundantly expressed in cardiac myocytes and metabolize arachidonic acid (AA) to four biologically active epoxyeicosatrienoic acid (EET) isomers (1Capdevila J.H. Falck J.R. Harris R.C. Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase.J. Lipid Res. 2000; 41: 163-181Abstract Full Text Full Text PDF PubMed Google Scholar). CYP epoxygenase-derived EETs have anti-inflammatory properties (2Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids.Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1011) Google Scholar) and have been reported to possess many potent biological effects in the renal and cardiovascular systems (3Miura H. Gutterman D.D. Human coronary arteriolar dilation to arachidonic acid depends on cytochrome P-450 monooxygenase and Ca2+-activated K+ channels.Circ. Res. 1998; 83: 501-507Crossref PubMed Scopus (131) Google Scholar, 4Fisslthaler B. Popp R. Kiss L. Potente M. Harder D.R. Fleming I. Busse R. Cytochrome P450 2C is an EDHF synthase in coronary arteries.Nature. 1999; 401: 493-497Crossref PubMed Scopus (804) Google Scholar–5Casolari C. Rossi T. Baggio G. Coppi A. Zandomeneghi G. Ruberto A.I. Farina C. Fabio G. Zanca A. Castelli M. Interaction between saquinavir and antimycotic drugs on C. albicans and C. neoformans strains.Pharmacol. Res. 2004; 50: 605-610Crossref PubMed Scopus (17) Google Scholar). For example, EETs inhibit cytokine-induced vascular cell adhesion molecule expression and leukocyte adhesion to the vascular wall (2Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids.Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1011) Google Scholar), inhibit vascular smooth muscle cell migration (6Sun J. Sui X. Bradbury J.A. Zeldin D.C. Conte M.S. Liao J.K. Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids.Circ. Res. 2002; 90: 1020-1027Crossref PubMed Scopus (150) Google Scholar), protect endothelial cells from apoptosis (7Yang S. Lin L. Chen J.X. Lee C.R. Seubert J.M. Wang Y. Wang H. Chao Z.R. Tao D.D. Gong J.P. et al.Cytochrome P-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-alpha via MAPK and PI3K/Akt signaling pathways.Am. J. Physiol. Heart Circ. Physiol. 2007; 293: H142-H151Crossref PubMed Scopus (108) Google Scholar), upregulate eNOS (8Jiang J.G. Chen R.J. Xiao B. Yang S. Wang J.N. Wang Y. Cowart L.A. Xiao X. Wang D.W. Xia Y. Regulation of endothelial nitric-oxide synthase activity through phosphorylation in response to epoxyeicosatrienoic acids.Prostaglandins Other Lipid Mediat. 2007; 82: 162-174Crossref PubMed Scopus (42) Google Scholar), and promote endothelial cell proliferation and angiogenesis via activation of MAP kinases and PI3 kinase/Akt signaling (8Jiang J.G. Chen R.J. Xiao B. Yang S. Wang J.N. Wang Y. Cowart L.A. Xiao X. Wang D.W. Xia Y. Regulation of endothelial nitric-oxide synthase activity through phosphorylation in response to epoxyeicosatrienoic acids.Prostaglandins Other Lipid Mediat. 2007; 82: 162-174Crossref PubMed Scopus (42) Google Scholar). 11,12- and 14,15-EETs have been characterized as effective mitogens (1Capdevila J.H. Falck J.R. Harris R.C. Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase.J. Lipid Res. 2000; 41: 163-181Abstract Full Text Full Text PDF PubMed Google Scholar, 9Chen J.K. Capdevila J. Harris R.C. Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells.Proc. Natl. Acad. Sci. USA. 2002; 99: 6029-6034Crossref PubMed Scopus (82) Google Scholar, 10Zhang C. Harder D.R. Cerebral capillary endothelial cell mitogenesis and morphogenesis induced by astrocytic epoxyeicosatrienoic acid.Stroke. 2002; 33: 2957-2964Crossref PubMed Scopus (100) Google Scholar, 11Medhora M. Daniels J. Mundey K. Fisslthaler B. Busse R. Jacobs E.R. Harder D.R. Epoxygenase-driven angiogenesis in human lung microvascular endothelial cells.Am. J. Physiol. Heart Circ. Physiol. 2003; 284: H215-H224Crossref PubMed Scopus (105) Google Scholar, 12Michaelis U.R. Fisslthaler B. Medhora M. Harder D. Fleming I. Busse R. Cytochrome P450 2C9-derived epoxyeicosatrienoic acids induce angiogenesis via cross-talk with the epidermal growth factor receptor (EGFR).FASEB J. 2003; 17: 770-772Crossref PubMed Scopus (149) Google Scholar, 13Pratt P.F. Medhora M. Harder D.R. Mechanisms regulating cerebral blood flow as therapeutic targets.Curr. Opin. Investig. Drugs. 2004; 5: 952-956PubMed Google Scholar–14Michaelis U.R. Falck J.R. Schmidt R. Busse R. Fleming I. Cytochrome P4502C9-derived epoxyeicosatrienoic acids induce the expression of cyclooxygenase-2 in endothelial cells.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 321-326Crossref PubMed Scopus (63) Google Scholar) that can enhance proliferation of renal epithelial cells (12Michaelis U.R. Fisslthaler B. Medhora M. Harder D. Fleming I. Busse R. Cytochrome P450 2C9-derived epoxyeicosatrienoic acids induce angiogenesis via cross-talk with the epidermal growth factor receptor (EGFR).FASEB J. 2003; 17: 770-772Crossref PubMed Scopus (149) Google Scholar, 15Graber M.N. Alfonso A. Gill D.L. Recovery of Ca2+ pools and growth in Ca2+ pool-depleted cells is mediated by specific epoxyeicosatrienoic acids derived from arachidonic acid.J. Biol. Chem. 1997; 272: 29546-29553Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 16Chen J.K. Capdevila J. Harris R.C. Overexpression of C-terminal Src kinase blocks 14, 15-epoxyeicosatrienoic acid-induced tyrosine phosphorylation and mitogenesis.J. Biol. Chem. 2000; 275: 13789-13792Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Interestingly, the role of 14,15-EET in mediating the mitogenic responses of EGF and HB-EGF has also been thoroughly documented in cultured LLCPk cells (9Chen J.K. Capdevila J. Harris R.C. Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells.Proc. Natl. Acad. Sci. USA. 2002; 99: 6029-6034Crossref PubMed Scopus (82) Google Scholar, 17Chen J.K. Wang D.W. Falck J.R. Capdevila J. Harris R.C. Transfection of an active cytochrome P450 arachidonic acid epoxygenase indicates that 14,15-epoxyeicosatrienoic acid functions as an intracellular second messenger in response to epidermal growth factor.J. Biol. Chem. 1999; 274: 4764-4769Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). CYP2J2 is abundantly expressed in the human myocardium; however, little is known about its role in the heart, especially in the context of heart failure. Seubert et al. recently demonstrated a protective role of CYP2J2 overexpression or exogenously administered EETs in ischemia-reperfusion injury in both rodents and dogs via a mechanism that involved opening of sarcolemmal and mitochondrial K+ channels and activation of p42/44 MAPK (18Seubert J. Yang B. Bradbury J.A. Graves J. Degraff L.M. Gabel S. Gooch R. Foley J. Newman J. Mao L. et al.Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K+ channels and p42/p44 MAPK pathway.Circ. Res. 2004; 95: 506-514Crossref PubMed Scopus (237) Google Scholar, 19Gross G.J. Falck J.R. Gross E.R. Isbell M. Moore J. Nithipatikom K. Cytochrome P450 and arachidonic acid metabolites: role in myocardial ischemia/reperfusion injury revisited.Cardiovasc. Res. 2005; 68: 18-25Crossref PubMed Scopus (101) Google Scholar). Importantly, the role of CYP2J2-derived EETs in nonischemic cardiac injury and dysfunction remains unknown. In the present study, neonatal rat cardiomyocytes were used to evaluate the effects of CYP2J2 overexpression and exogenous EET supplementation on tumor necrosis factor (TNF)-α–induced apoptosis and inflammation. An in vivo model of TNF-α–induced cardiac dysfunction was also utilized to evaluate the hypothesis that CYP2J2 could improve cardiac function by inhibiting myocardial inflammation and apoptosis. Recombinant adeno-associated virus vectors containing green fluorescent protein (GFP) or CYP2J2 were prepared as previously described (20Jiang J.G. Chen C.L. Card J.W. Yang S. Chen J.X. Fu X.N. Ning Y.G. Xiao X. Zeldin D.C. Wang D.W. Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors.Cancer Res. 2005; 65: 4707-4715Crossref PubMed Scopus (233) Google Scholar). CYP2J2 or the were prepared as described (2Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids.Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1011) Google Scholar, B. L. S. Falck J.R. Liao J.K. Zeldin D.C. Overexpression of cytochrome P450 CYP2J2 injury in cultured endothelial PubMed Scopus (149) Google Scholar). and were the to the cardiomyocytes were from rats as described previously H. C. Lee G. and Ca2+ signaling in neonatal rat cardiac J. Physiol. Physiol. 2007; PubMed Scopus Google Scholar). were by the of and with the of the and of cells were with TNF-α in the of exogenous or 14,15-EET or the CYP epoxygenase the cells were with or to with rat heart cells were from cells were with or with Transfection Molecular the was by cells a Transfection was expression of CYP2J2 was by and was with increased of EET the To the antiapoptotic of CYP2J2 or EETs and signaling cells were the EGFR or the PPARγ by with TNF-α protein kinase or receptor cells were with to TNF-α cell was an as described Y. X. Xiao X. R. Card J.W. Wang D.W. Zeldin D.C. acid epoxygenase metabolites endothelial cell growth and angiogenesis via protein kinase and signaling 2005; PubMed Scopus Google Scholar), and apoptosis was by flow In activity was by as a as described previously S. J. B. apoptosis in endothelial cells and cardiomyocytes is by and of and Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). were with in and and with and to the were with a flow cells were of apoptosis and or cells rats were from the of were by the of and with the of the and of were to and of or a of C. Wang Xiao X. Chao J. Chao L. Wang D.W. Zeldin D.C. with human and in 2003; PubMed Scopus Google Scholar) (2Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids.Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1011) Google Scholar). rats from a of TNF-α and TNF-α rats were by of X. L. S. J.M. with receptor in Res. PubMed Scopus Google Scholar) was the through the of and X. L. S. J.M. with receptor in Res. PubMed Scopus Google Scholar). and was used to to the as previously described (8Jiang J.G. Chen R.J. Xiao B. Yang S. Wang J.N. Wang Y. Cowart L.A. Xiao X. Wang D.W. Xia Y. Regulation of endothelial nitric-oxide synthase activity through phosphorylation in response to epoxyeicosatrienoic acids.Prostaglandins Other Lipid Mediat. 2007; 82: 162-174Crossref PubMed Scopus (42) Google Scholar). EETs can to by acid and in between and 14,15-EET of and 14,15-EET were expressed as of or levels of vascular cell adhesion molecule adhesion molecule and in were and to the Human endothelial cells were from human and of study, and was from were to the expressed in the of were with with TNF-α adhesion in blood cells were as previously described of the migration through cultured endothelial with necrosis Vasc. Res. 1999; PubMed Scopus Google Scholar, A. a of leukocyte with endothelial 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). from were and with the were with with TNF-α were to the and by with of was in on of For the of cells was and to cells the were the were to described previously H. Lin L. J. Wang Y. Bradbury J.A. Wang D.W. Zeldin D.C. of endothelial nitric-oxide synthase by factor involves protein kinase and protein kinase signaling 2003; PubMed Scopus (82) Google Scholar). were with and Akt and Akt and and PPARγ and epidermal growth factor receptor and EGFR the were with to was from CYP2J2 were as described previously S. C.R. Falck J.R. Zeldin D.C. Molecular and expression of a human cytochrome P450 arachidonic acid epoxygenase expressed in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and were from were expressed as between were by a of with the was as primary rat cardiomyocytes with CYP2J2 epoxygenase increased CYP2J2 expression and increased levels to cells with the levels were decreased by with TNF-α or showed that and 14,15-EET significantly decreased apoptosis of primary rat cardiomyocytes induced by TNF-α a CYP epoxygenase increased apoptosis with the cells Furthermore, CYP2J2 epoxygenase overexpression apoptosis and markedly TNF-α–induced apoptosis, an that was by flow from are in B. showed that exogenous EET and CYP2J2 overexpression in primary rat cardiomyocytes significantly the antiapoptotic proteins Bcl-2 and and the Furthermore, an antiapoptotic of CYP cells with increased CYP2J2 expression and increased levels to cells with These results are to previously reported endothelial cells (3Miura H. Gutterman D.D. Human coronary arteriolar dilation to arachidonic acid depends on cytochrome P-450 monooxygenase and Ca2+-activated K+ channels.Circ. Res. 1998; 83: 501-507Crossref PubMed Scopus (131) Google Scholar, 4Fisslthaler B. Popp R. Kiss L. Potente M. Harder D.R. Fleming I. Busse R. Cytochrome P450 2C is an EDHF synthase in coronary arteries.Nature. 1999; 401: 493-497Crossref PubMed Scopus (804) Google Scholar). results of demonstrate that of cells with was significantly cells with in both the and of TNF-α effects of CYP2J2 were significantly attenuated by both the EGFR and the PPARγ of to cells protective effects on cell in both the and of and these effects were attenuated by and These results that the effects of CYP2J2 overexpression and are in through activation of EGFR and We also the of EETs and CYP2J2 overexpression on apoptosis of cells by flow results that cells CYP2J2 significantly apoptosis TNF-α with cells with TNF-α supplementation with protective effects flow from are in B. antiapoptotic effects of CYP2J2 overexpression or exogenous supplementation were attenuated by both and These results that the antiapoptotic effects of CYP2J2 overexpression and are in through activation of EGFR and TNF-α of cells significantly increased Transfection with significantly attenuated the TNF-α–induced in with and cells was inhibited cells were with or supplementation with protective effects on activity in an that was also attenuated by and These results that the effects of CYP2J2 overexpression and on activity are in through activation of EGFR and of cells with exogenous significantly attenuated the of antiapoptotic proteins Bcl-2 and and prevented the of the protein that is normally observed TNF-α Overexpression of CYP2J2 effects on Bcl-xL, and expression Furthermore, the effects of and CYP2J2 overexpression were attenuated by of or the of EGFR and PPARγ in the of apoptosis signaling. TNF-α inhibited expression of and PI3K-dependent Akt CYP2J2 overexpression induced protein expression and Akt phosphorylation in both the and of TNF-α effects of CYP2J2 overexpression were inhibited cells were with or exogenous with increased Akt phosphorylation and an that was by both and of cells with TNF-α also to significantly phosphorylation of kinases and EGFR in CYP2J2 overexpression or exogenous significantly attenuated the TNF-α–induced effects on and EGFR phosphorylation and significantly and the protective effects of EETs on TNF-α–induced cell apoptosis Furthermore, the effects of CYP2J2 overexpression and on EGFR activation were inhibited by of also attenuated EGFR the effects were these that CYP2J2 overexpression or exogenous the signaling a that may involved in the antiapoptotic effects observed in cardiac CYP are known to possess potent anti-inflammatory of may mediated by activation of PPARγ of IκBα (2Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids.Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1011) Google Scholar, Y. Y. K. Lee X. Y. Gill S. C. et of the role of epoxyeicosatrienoic and Natl. Acad. Sci. USA. 2005; PubMed Scopus Google Scholar). Interestingly, CYP2J2 overexpression or of exogenous significantly PPARγ and both in the and of TNF-α These effects were significantly attenuated by of or to TNF-α the pathway may represent a novel protective pathway of TNF-α–induced effects in expression of CYP epoxygenases that CYP2J2 induced expression of CYP2J2 in vivo in the heart and Overexpression of CYP epoxygenases was with a in and 14,15-EET levels with levels in rats with or with These results that CYP2J2 induced epoxygenase expression and in activity in showed that TNF-α of rats induced a of cardiac function with rats with in a in and a in with and these results demonstrate an in and function CYP2J2 of CYP2J2 on in are expressed as in a are expressed as TNF-α significantly increased levels of and decreased levels of an anti-inflammatory Interestingly, the effects of TNF-α were markedly attenuated by CYP2J2 CYP2J2 overexpression inhibited TNF-α–induced expression in cultured TNF-α increased the of to was significantly attenuated by CYP2J2 overexpression In the present study, that CYP2J2 or exogenous of significantly cell and TNF-α–induced apoptosis in primary neonatal cardiomyocytes and in the rat cardiac cell Furthermore, CYP2J2 overexpression and exogenous of significantly the TNF-α–induced in activity and in expression of proteins Bcl-2 and Bcl-xL, a involves activation of and PPARγ signaling pathways. in vivo overexpression of CYP2J2 significantly inflammation and the cardiac dysfunction induced by apoptosis and inflammation induced by such as TNF-α are in the of and myocardial injury and heart injury apoptosis in PubMed Scopus Google Scholar, C. D. necrosis factor apoptosis in cardiac of the signaling in cardiac cell PubMed Scopus Google Scholar, T. in transgenic with overexpression of tumor necrosis Res. 1997; PubMed Google J.W. D.L. C. kinase myocardial 2005; PubMed Scopus Google Scholar). an role in the that a of heart to the of heart failure, a of apoptosis a of or can Importantly, cardiac myocytes are and have little as a a is to therapeutic heart that enhance cell and inhibit apoptosis. effects of and CYP2J2 overexpression that observed in are with the by Seubert et al. that CYP2J2 overexpression in transgenic postischemic myocardial dysfunction (18Seubert J. Yang B. Bradbury J.A. Graves J. Degraff L.M. Gabel S. Gooch R. Foley J. Newman J. Mao L. et al.Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K+ channels and p42/p44 MAPK pathway.Circ. Res. 2004; 95: 506-514Crossref PubMed Scopus (237) Google Scholar). EETs and CYP2J2 overexpression have also been to cytokine-induced endothelial cell adhesion molecule and EETs prevented leukocyte adhesion to the vascular wall by a mechanism factor and kinase (2Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids.Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1011) Google Scholar). also demonstrated effects of CYP2J2 overexpression on cytokine-induced leukocyte adhesion to endothelial In vivo showed that CYP2J2 overexpression of and enhancing of the anti-inflammatory In CYP2J2 via significantly increased CYP2J2 expression in vivo in heart, and (3Miura H. Gutterman D.D. Human coronary arteriolar dilation to arachidonic acid depends on cytochrome P-450 monooxygenase and Ca2+-activated K+ channels.Circ. Res. 1998; 83: 501-507Crossref PubMed Scopus (131) Google Scholar, C. Rossi T. Baggio G. Coppi A. Zandomeneghi G. Ruberto A.I. Farina C. Fabio G. Zanca A. Castelli M. Interaction between saquinavir and antimycotic drugs on C. albicans and C. neoformans strains.Pharmacol. Res. 2004; 50: 605-610Crossref PubMed Scopus (17) Google Scholar, J. Sui X. Bradbury J.A. Zeldin D.C. Conte M.S. Liao J.K. Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids.Circ. Res. 2002; 90: 1020-1027Crossref PubMed Scopus (150) Google Scholar, B. X. J. X. Yang G. Xiao X. J.W. Zeldin D.C. Wang D.W. Overexpression of cytochrome P450 epoxygenases of in rats by enhancing PubMed Scopus Google Scholar, C. Wang L. R. B. L. X. Zeldin D.C. Wang D.W. of cytochrome p450 epoxygenase in J. Biol. PubMed Scopus Google Scholar), may also effects of heart These results the that CYP2J2-derived EETs protect the heart via anti-inflammatory, antiapoptotic, and effects. demonstrate an role PPARγ and EGFR signaling in mediating the effects of EETs and CYP2J2 of cells with PPARγ or EGFR significantly inhibited the antiapoptotic and effects of and CYP2J2 overexpression, with EGFR especially These results demonstrate that EGFR and PPARγ signaling is an in cardiac apoptosis and enhancing survival. These results are by studies in cell EGFR in response to EET (9Chen J.K. Capdevila J. Harris R.C. Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells.Proc. Natl. Acad. Sci. USA. 2002; 99: 6029-6034Crossref PubMed Scopus (82) Google Scholar, L.M. J.G. Chen C. Zeldin D.C. Wang D.W. epoxyeicosatrienoic phosphorylation of involves the activation of and the of HB-EGF in PubMed Scopus (17) Google Scholar). 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Wang D.W. epoxyeicosatrienoic phosphorylation of involves the activation of and the of HB-EGF in PubMed Scopus (17) Google Scholar). these that PPARγ activation role in In study, CYP2J2 overexpression or EET PPARγ PPARγ on EGFR These results that PPARγ in heart may have cross-talk with EGFR In demonstrated that overexpression of epoxygenases can blood in rats via enhancing in cardiomyocytes B. X. J. X. Yang G. Xiao X. J.W. Zeldin D.C. Wang D.W. Overexpression of cytochrome P450 epoxygenases of in rats by enhancing PubMed Scopus Google Scholar) and can with significantly decreased in EETs protect endothelial cells from apoptosis and increased eNOS activity and expression X. Wang D.W. of epoxygenases and epoxyeicosatrienoic in cardiovascular and PubMed Scopus Google Scholar). Liao demonstrated that EETs inhibited leukocyte adhesion to endothelial cells and via of in endothelial cells (2Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids.Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1011) Google Scholar). These that EETs have effects and that these cardiovascular protective effects to effects on the heart, especially by In the present study, blood was overexpression of epoxygenase has Further studies are to effects of EETs in and activation of and role via as as and of In the present on the protective role of EETs cardiac dysfunction and myocardial of cardiac that CYP2J2 expression and EET in the are protective are mediated via EGFR and PPARγ the of to enhance EETs to exogenous EETs as a novel approach to the of cardiovascular heart failure. with arachidonic acid adeno-associated protein kinase cytochrome P450 2J2 epoxyeicosatrienoic acid epidermal growth factor receptor kinase green fluorescent protein human endothelial cell adhesion of protein kinase endothelial nitric-oxide synthase blood cell receptor acid tumor necrosis vascular cell adhesion

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