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

Zhao, Gang; Wang, Jia‐Ning; Xu, Xizhen; Jing, Yanyan; Tu, Lei; Li, Xuguang; Chen, Chen; Cianflone, Katherine; Wang, Peihua; Dackor, Ryan T.; Zeldin, Darryl C.; Wang, Dao Wen

doi:10.1194/jlr.m017319

Cited by 54 publications

(45 citation statements)

References 44 publications

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“…Recent studies have demonstrated that EETs suppress the infl ammatory response in vitro and in vivo ( 5,40,41 ), and we recently reported that CYP2J2 overexpression reduced infl ammatory responses and protected against heart and renal injury ( 12,19 ). Consistent with a previous study of the s-EH inhibitor ( 14 ), our work demonstrates that CYP2J2 overexpression has a substantial inhibitory effect on vascular infl ammation, which is considered to be the major mechanism of Ang II-induced AAA development ( 4,20 ).…”

Section: Discussionsupporting

confidence: 79%

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: Discussionsupporting

confidence: 79%

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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“…It has been documented that CYP2J2 is predominantly expressed in human cardiomyocytes and endothelial cells [13,29]. Based on previous studies [13,14], we chose the pcDNA3.1 plasmid as a vector to transfect CYP2J2. Immunohistochemical staining confirmed that CYP2J2 expression was remarkably elevated in lung tissues of transgenic rats, especially in vascular endothelial cells and epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate the in vivo EETs level, an ELISA kit (Detroit R&D, Detroit, MI) was used to determine the concentrations of 14,15-DHET in the rat serum and lung homogenates according to the manufacturer's instructions, as previously described [14,19,24]. …”

Section: Methodsmentioning

confidence: 99%

“…Among these, CYP2J2 is expressed in humans, mainly in the cardiovascular system [12]. In previous studies, EETs have been reported to exert diverse biological effects in the cardiovascular and renal systems, such as anti-inflammatory, anti-apoptotic, pro-proliferation, pro-angiogenesis, anti-oxidation, anti-fibrosis, and anti-hypertension effects [13,14,15,16,17,18]. …”

Section: Introductionmentioning

confidence: 99%

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CYP2J2 and EETs Protect against Oxidative Stress and Apoptosisin Vivoandin VitroFollowing Lung Ischemia/Reperfusion

Chen

Zheng

Yang

et al. 2014

Cell Physiol Biochem

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Background: Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to epoxyeicosatrienoic acids (EETs). EETs exert various biological effects, including anti-inflammatory, anti-apoptotic, pro-proliferation, pro-angiogenesis, anti-oxidation, and anti-fibrosis effects. However, little is known about the role of CYP2J2 and EETs in lung ischemia/reperfusion injury. In this study, we examined the effects of exogenous EETs or CYP2J2 overexpression on lung ischemia/reperfusion injury in vivo and in vitro. Methods and Results: CYP2J2 gene was stably transfected into rat lungs via pcDNA3.1-CYP2J2 plasmid delivery, resulting in increased EETs levels in the serum and lung. A rat model of lung ischemia/reperfusion injury was developed by clamping the left lung hilum for 1 hour, followed by reperfusion for 2 hours. We found that CYP2J2 overexpression markedly decreased the levels of oxidative stress and cell apoptosis in lung tissues induced by ischemia/reperfusion. Moreover, we observed that exogenous EETs, or CYP2J2 overexpression, enhanced cell viability, decreased intracellular reactive oxygen species (ROS) generation, inhibited mitochondrial dysfunction, and attenuated several apoptotic signaling events in a human pulmonary artery endothelial cells (HPAECs)-based anoxia/reoxygenation model. These apoptotic events included activation of NADPH oxidase, collapse of mitochondrial transmembrane potential, and activation of pro-apoptotic proteins and caspase-3. These effects were mediated, at least partially, by the PI3K/Akt signaling pathway. Conclusion: These results reveal that CYP2J2 overexpression and exogenous EETs can protect against oxidative stress and apoptosis following lung ischemia/reperfusion in vivo and in vitro, suggesting that increasing the level of EETs may be a novel promising strategy to prevent and treat lung ischemia/reperfusion injury.

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“…CYP2J2 is abundantly expressed in the human myocardium and metabolizes arachidonic acid (AA) to four biologically active epoxyeicosatrienoic acid (EET) regioisomers (5,8,11,and 14, (Zhao et al, 2012). Over the past 2 decades, it has become increasingly evident that CYP2J2-derived EETs exert many protective effects on the cardiovascular system.…”

Section: Introductionmentioning

confidence: 99%

CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

Wang

Yang

et al. 2013

Mol Pharmacol

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Prolonged endoplasmic reticulum (ER) stress causes apoptosis and is associated with heart failure. Whether CYP2J2 and its arachidonic acid metabolites [epoxyeicosatrienoic acids (EETs)] have a protective influence on ER stress and heart failure has not been studied. Assays of myocardial samples from patients with end-stage heart failure showed evidence of ER stress. Chronic infusion of isoproterenol (ISO) or angiotensin II (AngII) by osmotic mini-pump induced cardiac hypertrophy and heart failure in mice as evaluated by hemodynamic measurements and echocardiography. Interestingly, transgenic (Tr) mice with cardiomyocyte-specific CYP2J2 expression were protected against heart failure compared with wild-type mice. ISO or AngII administration induced ER stress and apoptosis, and increased levels of intracellular Ca 21 . These phenotypes were abolished by CYP2J2 overexpression in vivo or exogenous EETs treatment of cardiomyocytes in vitro. ISO or AngII reduced sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) expression in hearts or isolated cardiomyocytes; however, loss of SERCA2a expression was prevented in CYP2J2 Tr hearts in vivo or in cardiomyocytes treated with EETs in vitro. The reduction of SERCA2a activity was concomitant with increased oxidation of SERCA2a. EETs reversed SERCA2a oxidation through increased expression of antioxidant enzymes and reduced reactive oxygen species levels. Tempol, a membrane-permeable radical scavenger, similarly decreased oxidized SERCA2a levels, restored SERCA2a activity, and markedly reduced ER stress response in the mice treated with ISO. In conclusion, CYP2J2-derived EETs suppress ER stress response in the heart and protect against cardiac failure by maintaining intracellular Ca 21 homeostasis and SERCA2a expression and activity.

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

Cited by 54 publications

References 44 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

CYP2J2 and EETs Protect against Oxidative Stress and Apoptosisin Vivoandin VitroFollowing Lung Ischemia/Reperfusion

CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

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