CYP2J2-derived EETs attenuated ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis

Zhou, Chi; Huang, Jin Long; Li, Qing; Zhan, Chenao; Xu, Xizhen; Zhang, Xu; Ai, Ding; Zhu, Yi; Wen, Zheng; Wang, Dao Wen

doi:10.1016/j.freeradbiomed.2018.02.009

Cited by 45 publications

(33 citation statements)

References 43 publications

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“…In agreement with previous study, AAV9‐2J2 improved the worsened cardiac function in AAC mice, as demonstrated in Figure C,D (heart weight/body weight ratio (HW/BW) and ejection fraction (EF)); therefore, the effects of CYP2J2 observed in the atria may be secondary to the improvement in cardiac function. To investigate the mechanisms that CYP2J2/EET inhibits atrial fibrosis and independent of cardiac function, and to assess the role of Smad‐7, the isolated atrial fibroblasts were treated with 11,12‐EET (1000 nmol L −1 ), 14,15‐EEZE (1000 nmol L −1 , EET antagonist), GW9662 (1000 nmol L −1 ) and Smad‐7 SiRNA in the presence of TGF‐β1 (10 ng/mL), as TGF‐β1 is the most important profibrotic stimulators for cardiac fibroblasts.…”

Section: Resultssupporting

confidence: 92%

“…In agreement with previous study, 10,11 AAV9-2J2 improved the worsened cardiac function in AAC mice, as demonstrated in Figure S2C,D (heart weight/body weight ratio (HW/BW) and ejection fraction (EF)); therefore, the effects of CYP2J2 observed in the atria may be secondary to the improvement in cardiac function.…”

Section: Epoxyeicosatrienoic Acid Suppress Tgf-βinduced Atrial Fibrsupporting

confidence: 92%

“…EET is a pleiotropic cytokine that regulates a wide range of cellular actions and pathophysiological processes; in particular, the studies of EET in the cardiovascular system have become increasingly appreciated in recent years . Notably, CYP2J2/EET was recently demonstrated to prevent cardiac fibrosis . Meanwhile, the anti‐inflammatory properties of CYP epoxygenase‐derived EET have been well evidenced ; further, we found that CYP2J2/EET inhibited TNF‐α‐induced cardiac injury by attenuation of nuclear factor‐kappaB activation .…”

Section: Introductionmentioning

confidence: 64%

“…9 Notably, CYP2J2/EET was recently demonstrated to prevent cardiac fibrosis. 10,11 Meanwhile, the anti-inflammatory properties of CYP epoxygenase-derived EET have been well evidenced 12,13 ; further, we found that CYP2J2/EET inhibited TNF-α-induced cardiac injury by attenuation of nuclear factor-kappaB activation. 14 These protective effects might be mediated by peroxisome proliferator-activated receptor gamma (PPAR-γ), an important effector of EET.…”

mentioning

confidence: 76%

“…3,6 CYP2J2 is a cytochrome P450 epoxygenase that is abundantly expressed in the human heart. CYP2J2 converts arachidonic acid to the four regioisomeric epoxyeicosatrienoic acids (5,8,11,, and EETs are further metabolized by the soluble epoxide hydrolase enzyme to form the corresponding 1,2diols, hydroxyeicosatetraenoic acids (DHET) with diminished bioactivity. 8 EET is a pleiotropic cytokine that regulates a wide range of cellular actions and pathophysiological processes; in particular, the studies of EET in the cardiovascular system have become increasingly appreciated in recent years.…”

mentioning

confidence: 99%

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CYP2J2/EET reduces vulnerability to atrial fibrillation in chronic pressure overload mice

Zhu

Meng

et al. 2019

J Cellular Molecular Medi

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Growing evidence has well established the protective effects of CYP2J2/EET on the cardiovascular system. The aim of the present study was to determine whether CYP2J2/EET has a preventive effect on atrial fibrillation (AF) and to investigate the underlying mechanisms. Wild‐type mice were injected with or without AAV9‐CYP2J2 before abdominal aortic constriction (AAC) operation. After 8 weeks, compared with wild‐type mice, AAC mice display higher AF inducibility and longer AF durations, which were remarkably attenuated with AAV9‐CYP2J2. Also, AAV9‐CYP2J2 reduced atrial fibrosis area and the deposit of collagen‐I/III in AAC mice, accompanied by the blockade of TGF‐β/Smad‐2/3 signalling pathways, as well as the recovery in Smad‐7 expression. In vitro, isolated atrial fibroblasts were administrated with TGF‐β1, EET, EEZE, GW9662, SiRNA Smad‐7 and pre‐MiR‐21, and EET was demonstrated to restrain the differentiation of atrial fibroblasts largely dependent on Smad‐7, due to the inhibition of EET on MiR‐21. In addition, increased inflammatory cytokines, as well as activated NF‐κB pathways induced by AAC surgery, were also significantly blunted by AAV9‐CYP2J2 treatment. These effects of CYP2J2/EET were partially blocked by GW9662, the antagonist of PPAR‐γ. In conclusion, this study revealed that CYP2J2/EET ameliorates atrial fibrosis through modulating atrial fibroblasts activation by disinhibition of MiR‐21 on Smad‐7, and attenuates atrial inflammatory response by repressing NF‐κB pathways, reducing the vulnerability to AF, and CYP2J2/EET exerts its role at least partially through PPAR‐γ activation. Our findings might provide a novel upstream therapeutic strategy for AF.

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Section: Resultssupporting

confidence: 92%

Section: Epoxyeicosatrienoic Acid Suppress Tgf-βinduced Atrial Fibrsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 64%

mentioning

confidence: 76%

mentioning

confidence: 99%

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CYP2J2/EET reduces vulnerability to atrial fibrillation in chronic pressure overload mice

Zhu

Meng

et al. 2019

J Cellular Molecular Medi

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Drug‐Metabolizing Enzymes and Drug Toxicity

2021

Transporters and Drug‐Metabolizing Enzymes in Drug Toxicity

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Targeting Soluble Epoxide Hydrolase with TPPU Alleviates Irradiation‐Induced Hyposalivation in Mice via Preventing Apoptosis and Microcirculation Disturbance

Zhang

Bai

et al. 2020

Advanced Therapeutics

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IR irradiation-induced dysfunction of the salivary gland and hyposalivation are one of the main complications of radiotherapy treatment for malignant head and neck tumors, and its mechanisms are not fully understood. IR-induced microcirculation disturbance and apoptosis is one of the most important mechanisms. Most recent studies have focused on the regenerative effects of epoxyeicosatrienoic acids (EETs) through the process of increased angiogenesis. This study suggests that increasing endogenous EETs by the soluble epoxide hydrolase (sEH) inhibitor TPPU can reverse dysfunctional salivary glands and hyposalivation by improving the associated microenvironment and tissue regeneration. The findings suggest that TPPU alleviates hyposalivation and histological lesions, increases angiogenesis and reduces apoptosis of acinar cells significantly in IR-damaged mice. The results in vitro demonstrate that TPPU promotes the proliferation and inhibits apoptosis of human salivary gland (HSG) cells, and enhances the motility and angiogenesis of human umbilical vein endothelial cells (HUVECs). The results also suggest that TPPU-induced synergy and crosstalk between acinar cells and vascular endothelial cells might contribute to angiogenesis. Together, this study proves the feasibility of targeting sEH using TPPU to promote angiogenesis and reduce apoptosis, and also indicates the potential of sEH inhibitors for functional reconstruction of IR-induced salivary glands damage.

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CYP2J2-derived EETs attenuated ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis

Cited by 45 publications

References 43 publications

CYP2J2/EET reduces vulnerability to atrial fibrillation in chronic pressure overload mice

CYP2J2/EET reduces vulnerability to atrial fibrillation in chronic pressure overload mice

Drug‐Metabolizing Enzymes and Drug Toxicity

Targeting Soluble Epoxide Hydrolase with TPPU Alleviates Irradiation‐Induced Hyposalivation in Mice via Preventing Apoptosis and Microcirculation Disturbance

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