Endothelium-specific CYP2J2 overexpression improves cardiac dysfunction by promoting angiogenesis via Jagged1/Notch1 signaling

Zhao, Qinshuo; Huang, Jingqiu; Wang, Dong; Chen, Liang; Sun, Dating; Zhao, Chunxia

doi:10.1016/j.yjmcc.2018.08.027

Cited by 33 publications

(29 citation statements)

References 42 publications

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“…Our results indicated that CYP2J2-transgenic rats that underwent retinal I/R exhibited higher RGC survival rates than wild types. These results coincide with previous studies that postulate the protective role of CYP2J2 in I/R injuries (19)(20)(21). Antisenescence is conceivably one of the protective mechanisms, but likely not the only one.…”

Section: Discussionsupporting

confidence: 92%

“…Senescence is a cellular state in which cells remain viable with permanent cell cycle arrest. Senescence is prompted by various stresses, including telomeric dysfunction, mitochondrial deterioration, and oxidative stress (19). Senescent cells are characterized by increased enzymatic activity of SA-b-gal and upregulation of the p53 and p16 pathways.…”

Section: Discussionmentioning

confidence: 99%

“…CYP2J2 and EETs protect against I/R injuries both in vivo and in vitro. In vivo, endothelium-specific CYP2J2 overexpression with enhanced EET activity has been reported to alleviate tissue damage caused by I/R injury in heart, lung, and brain tissues (19)(20)(21). In vitro experiments showed that forced expression of CYP2J2 in cultured bovine aortic endothelial cells attenuated hypoxia-reoxygenation-induced endothelial injuries (22).…”

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confidence: 99%

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The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

et al. 2019

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Glaucoma is a leading cause of irreversible blindness worldwide. Vascular factors play a substantial role in the pathogenesis of glaucoma. Expressed in the vascular endothelium, cytochrome P450 (CYP) 2J2 is one of the CYP epoxygenases that metabolize arachidonic acid to produce epoxyeicosatrienoic acids and exert pleiotropic protective effects on the vasculature. In the present study, we investigated whether endothelium‐specific over‐expression of CYP2J2 (tie2‐CYP2J2‐Tr) protects against retinal ganglion cell (RGC) loss induced by glaucoma and in what way retinal vessels are involved in this process. We used a glaucoma model of retinal ischemia‐reperfusion (I/R) injury in rats and found that endothelium‐specific overexpression of CYP2J2 attenuated RGC loss induced by retinal I/R. Moreover, retinal I/R triggered retinal vascular senescence, indicated by up‐regulated senescence‐related proteins p53, p16, and β‐galactosidase activity. The senescent endothelial cells resulted in pericyte loss and increased endothelial secretion of matrix metallopeptidase 9, which further contributed to RGC loss. CYP2J2 overexpression alleviated vascular senescence, pericyte loss, and matrix metallopeptidase 9 secretion. CYP2J2 suppressed endothelial senescence by down‐regulating senescence‐associated proteins p53 and p16. These 2 proteins were positively regulated by microRNA‐128‐3p, which was inhibited by CYP2J2. These results suggest that CYP2J2 protects against endothelial senescence and RGC loss in glaucoma, a discovery that may lead to the development of a potential treatment strategy for glaucoma.—Huang, J., Zhao, Q., Li, M., Duan, Q., Zhao, Y., Zhang, H. The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model. FASEB J. 33, 11194–11209 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

et al. 2019

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“…Rats possess larger body size and have more body fluids, which are conducive to DMPK studies (Lu et al, 2017). Moreover, it is reported that the rat model shows advantages over mouse model for the study of cardiovascular diseases (Iannaccone and Jacob, 2009;Zhao et al, 2018). As the third generation of artificial nuclease technology, the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) system has become the most important gene editing tool (Shao et al, 2014;Wang et al, 2016).…”

Section: Downloaded Frommentioning

confidence: 99%

“…Epoxyeicosatrienoic acids (EETs) are derived from CYP2J2-mediated AA metabolism (Chen et al, 2011). CYP2J2 can protect cardiac function in myocardial infarction-induced heart failure by increasing the concentration of circulating EETs and promoting angiogenesis through Jagged1/Notch1 signaling pathway (Zhao et al, 2018). In addition, CYP2J2 inhibitor can significantly reduce the proliferation, migration and promote apoptosis of tumor cells by inhibiting the biosynthesis of EETs (Lu et al, 2018;Chen et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Generation and Characterization of Cytochrome P450 2J3/10 CRISPR/Cas9 Knockout Rat Model

Chen

et al. 2020

Drug Metab Dispos

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Cytochrome P450 2J2 (CYP2J2) enzyme attracts more attention because it not only metabolizes clinical drugs, but also mediates the biotransformation of important endogenous substances and the regulation of physiological function. Although CYP2J2 is very important, few animal models are available to study its function in vivo. In particular, CYP2J gene knockout (KO) rat model for drug metabolism and pharmacokinetics is not available. In this report, the CRISPR/Cas9 technology was used to delete rat CYP2J3/10, the orthologous genes of CYP2J2 in humans. The CYP2J3/10 KO rats were viable and fertile and showed no any off-target effect. Compared with wild-type (WT) rats, the mRNA and protein expression of CYP2J3/10 in liver, small intestine and heart of KO rats were completely absent. At the same time, CYP2J4 mRNA expression and protein expression were significantly decreased in these tissues. Further in vitro and in vivo metabolic studies of astemizole, a typical substrate of CYP2J, indicated that CYP2J was functionally inactive in KO rats. The heart function indexes of WT and KO rats were also measured and compared. The myocardial enzymes including creatine kinase-muscle brain type (CK-MB), creatine kinase (CK) and CK-MB/CK ratio of KO rats increased by nearly 140%, 80%, and 60%, respectively. In conclusion, this study successfully developed a new CYP2J3/10 KO rat model, which is a useful tool to study the function of CYP2J in drug metabolism and cardiovascular disease.

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Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology

Hsu

2021

Advanced Biology

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Pharmacotherapy has been serving as an effective treatment for HFs to improve symptom, functional capacity, quality of life, and to reduce the frequency of hospitalizations. [8] However, it differs in each HF subtype. Traditionally, angiotensin converting enzyme inhibitors (ACEIs), mineralocorticoid receptor antagonists (MRAs), and β-blockers are typical treatments for HFrEF. Since many hospitalizations and deaths in HFpEF patients are due to noncardiovascular causes, pharmacotherapy mainly focus on relieving of symptoms and easing comorbidities for HFpEF patients.HFpEF with a prevalence range from 31% to 55% has received most attention recently from the clinical and research field [4,9,10] due to lack of effective pharmacological treatment options. Although cardiac regenerative therapeutics have been widely studied in the past two decades [11] for treating both HFrEF and HFpEF, the treatment mechanisms and associated intrinsic cardiac remodeling process are nonspecific to each HF subtype. Besides, additional mechanisms such as metabolic disorders, proinflammatory conditions, and immunologic remodeling also influenced the prognosis of different HFs. [12] In this review, we summarized pathological cardiac remodeling, associated immune reactions, and signaling pathways for HF in general, and discussed the challenges that hamper clinical translation of regenerative therapeutics which holds diagnostic and therapeutic potential. This review helps to reveal the underlying mechanisms that may lead us to generate new clinical-feasible treatment for HFpEF in the future. [13][14][15][16][17][18] Signaling during HF Progression HF ProgressionThe growth of cardiomyocytes occurs in both physiological and pathological hypertrophy. [19] Physiologically, hemodynamic load stimulates normal, postnatal, pregnancy, and exercise-induced cardiac growth. [19] Pathologically, the stimulation from HF risk factors increases heart size, mass, or geometry. In the progression of HF, multiple molecular mechanisms associated with cardiomyocyte survival, death, energy metabolism, oxidative stress, inflammation, calcium transport and neurohormonal activation led to loss of functional cardiomyocytes, development of fibrosis, left ventricular remodeling, and HF prognosis. [20] Heart failure (HF) is one of the leading causes for hospital admissions worldwide. HF patients are classified based on the chronic changes in left ventricular ejection fraction (LVEF) as preserved (LVEF ≥ 50%), reduced (LVEF ≤ 40%), or mid-ranged (40% < LVEF < 50%) HFs. Treatments nowadays can prevent HFrEF progress, whereas only a few of the treatments have been proven to be effective in improving the survival of HFpEF. In this review, numerous mediators involved in the pathogenesis of HF are summarized. The regional upstream signaling and their diagnostic and therapeutic potential are also discussed. Additionally, the recent challenges and development in cardiac regenerative therapy that hold opportunities for future research and clinical translation are discussed.

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Endothelium-specific CYP2J2 overexpression improves cardiac dysfunction by promoting angiogenesis via Jagged1/Notch1 signaling

Cited by 33 publications

References 42 publications

The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

Generation and Characterization of Cytochrome P450 2J3/10 CRISPR/Cas9 Knockout Rat Model

Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology

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