Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart

被引：103

作者：

Edin, Matthew L. ^{[1
]}

Wang, ZhongJing ^{[1
]}

Bradbury, J. Alyce ^{[1
]}

Graves, Joan P. ^{[1
]}

Lih, Fred B. ^{[1
]}

DeGraff, Laura M. ^{[1
]}

Foley, Julie F. ^{[1
]}

Torphy, Robert ^{[1
]}

Ronnekleiv, Oline K. ^{[2
,3
]}

Tomer, Kenneth B. ^{[1
]}

Lee, Craig R. ^{[4
]}

Zeldin, Darryl C. ^{[1
]}

机构：

[1] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA

[2] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA

[3] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97201 USA

[4] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA

来源：

FASEB JOURNAL | 2011年 / 25卷 / 10期

关键词：

CYP2J2; EETs; reactive oxygen species; leukotoxin; Langendorff; SOLUBLE EPOXIDE HYDROLASE; EPOXYEICOSATRIENOIC ACIDS; ARACHIDONIC-ACID; LINOLEIC-ACID; MYOCARDIAL-INFARCTION; POSTISCHEMIC RECOVERY; ATHEROSCLEROSIS RISK; CONTRACTILE FUNCTION; GENETIC-VARIATION; DISEASE RISK;

D O I：

10.1096/fj.11-188300

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cytochrome P450 (CYP) epoxygenases CYP2C8 and CYP2J2 generate epoxyeicosatrienoic acids (EETs) from arachidonic acid. Mice with expression of CYP2J2 in cardiomyocytes (alpha MHC-CYP2J2 Tr) or treated with synthetic EETs have increased functional recovery after ischemia/reperfusion (I/R); however, no studies have examined the role of cardiomyocyte-vs. endothelial-derived EETs or compared the effects of different CYP epoxygenase isoforms in the ischemic heart. We generated transgenic mice with increased endothelial EET biosynthesis (Tie2-CYP2C8 Tr and Tie2-CYP2J2 Tr) or EET hydrolysis (Tie2-sEH Tr). Compared to wild-type (WT), alpha MHC-CYP2J2 Tr hearts showed increased recovery of left ventricular developed pressure (LVDP) and decreased infarct size after I/R. In contrast, LVDP recovery and infarct size were unchanged in Tie2-CYP2J2 Tr and Tie2-sEH Tr hearts. Surprisingly, compared to WT, Tie2-CYP2C8 Tr hearts had significantly reduced LVDP recovery (from 21 to 14%) and increased infarct size after I/R (from 51 to 61%). Tie2-CYP2C8 Tr hearts also exhibited increased reactive oxygen species (ROS) generation, dihydroxyoctadecenoic acid (DiHOME) formation, and coronary resistance after I/R. ROS scavengers and CYP2C8 inhibition reversed the detrimental effects of CYP2C8 expression in Tie2-CYP2C8 Tr hearts. Treatment of WT hearts with 250 nM 9,10-DiHOME decreased LVDP recovery compared to vehicle (16 vs. 31%, respectively) and increased coronary resistance after I/R. These data demonstrate that increased ROS generation and enhanced DiHOME synthesis by endothelial CYP2C8 impair functional recovery and mask the beneficial effects of increased EET production following I/R.-Edin, M. L., Wang, Z. J., Bradbury, J. A., Graves, J. P., Lih, F. B., DeGraff, L. M., Foley, J. F., Torphy, R., Ronnekleiv, O. K., Tomer, K. B., Lee, C. R., Zeldin, D. C. Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart. FASEB J. 25, 3436-3447 (2011). www.fasebj.org

引用

页码：3436 / 3447

页数：12

共 56 条

[1] Analysis of cytochrome P450 metabolites of arachidonic and linoleic acids by liquid chromatography mass spectrometry with ion trap MS2 [J].

Bylund, J ;

Ericsson, J ;

Oliw, EH .

ANALYTICAL BIOCHEMISTRY, 1998, 265 (01) :55-68

[2] Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors [J].

Campbell, WB ;

Gebremedhin, D ;

Pratt, PF ;

Harder, DR .

CIRCULATION RESEARCH, 1996, 78 (03) :415-423

[3] Inhibition of Soluble Epoxide Hydrolase by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid Is Protective Against Ischemia-Reperfusion Injury [J].

Chaudhary, Ketul R. ;

Abukhashim, Mohamed ;

Hwang, Sung Hee ;

Hammock, Bruce D. ;

Seubert, John M. .

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 2010, 55 (01) :67-73

[4] Role of B-type natriuretic peptide in epoxyeicosatrienoic acid-mediated improved post-ischaemic recovery of heart contractile function [J].

Chaudhary, Ketul R. ;

Batchu, Sri Nagarjun ;

Das, Dipankar ;

Suresh, Mavanur R. ;

Falck, John R. ;

Graves, Joan P. ;

Zeldin, Darryl C. ;

Seubert, John M. .

CARDIOVASCULAR RESEARCH, 2009, 83 (02) :362-370

[5] Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells [J].

Chen, JK ;

Capdevila, J ;

Harris, RC .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (09) :6029-6034

[6] Inhibition of cardiac L-type calcium channels by epoxyeicosatrienoic acids [J].

Chen, JY ;

Capdevila, JH ;

Zeldin, DC ;

Rosenberg, RL .

MOLECULAR PHARMACOLOGY, 1999, 55 (02) :288-295

[7]

DAIKH BE, 1994, J PHARMACOL EXP THER, V271, P1427

[8] Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice [J].

Deng, Yangmei ;

Edin, Matthew L. ;

Theken, Katherine N. ;

Schuck, Robert N. ;

Flake, Gordon P. ;

Kannon, M. Alison ;

DeGraff, Laura M. ;

Lih, Fred B. ;

Foley, Julie ;

Bradbury, J. Alyce ;

Graves, Joan P. ;

Tomer, Kenneth B. ;

Falck, John R. ;

Zeldin, Darryl C. ;

Lee, Craig R. .

FASEB JOURNAL, 2011, 25 (02) :703-713

[9] Endothelium-derived hyperpolarizing factor synthase (cytochrome P4502C9) is a functionally significant source of reactive oxygen species in coronary arteries [J].

Fleming, I ;

Michaelis, UR ;

Bredenkötter, D ;

Fisslthaler, B ;

Dehghani, F ;

Brandes, RP ;

Busse, R .

CIRCULATION RESEARCH, 2001, 88 (01) :44-51

[10] CARDIOVASCULAR EFFECTS OF LEUKOTOXIN (9,10-EPOXY-12-OCTADECENOATE) AND FREE FATTY-ACIDS IN DOGS [J].

FUKUSHIMA, A ;

HAYAKAWA, M ;

SUGIYAMA, S ;

AJIOKA, M ;

ITO, T ;

SATAKE, T ;

OZAWA, T .

CARDIOVASCULAR RESEARCH, 1988, 22 (03) :213-218

← 1 2 3 4 5 6 →