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.
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Gang
G
Zhao
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Jianing
J
Wang
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Xizhen
X
Xu
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Yanyan
Y
Jing
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China. Electronic address: proftu@tom.com.
Ling
L
Tu
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Xuguang
X
Li
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Chen
C
Chen
Centre de Recherche Institut Universitaire de Cardiologie et Pneumologie de Quebec Universite Laval, Québec City, Québec G1V 4G5, Canada.
Katherine
K
Cianflone
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Peihua
P
Wang
Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Ryan T
RT
Dackor
Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Darryl C
DC
Zeldin
Department of Internal Medicine and Gene Therapy Center Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China; Centre de Recherche Institut Universitaire de Cardiologie et Pneumologie de Quebec Universite Laval, Québec City, Québec G1V 4G5, Canada. Electronic address: dwwang@tjh.tjmu.edu.cn.
Dao Wen
DW
Wang
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000652:urine; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D015777:Eicosanoids; D005434:Flow Cytometry; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
C107016:14,15-dihydroxyeicosatrienoic acid; D015777:Eicosanoids; D047492:Peroxisome Proliferator-Activated Receptors; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D015126:8,11,14-Eicosatrienoic Acid