Qinshuo Zhao1, Jingqiu Huang2, Dong Wang3, Liang Chen4, Dating Sun4, Chunxia Zhao5. 1. Division of Cardiology, Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China. Electronic address: QinshuoZhao1030@126.com. 2. Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 3. Department of Cardiology, Wuhan No.1 Hospital, Huazhong University of Science and Technology, Wuhan, China. 4. Division of Cardiology, Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China. 5. Division of Cardiology, Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China. Electronic address: Zhaocx@tjh.tjmu.edu.cn.
Abstract
BACKGROUND: Myocardial infarction (MI) contributes to the development of cardiac remodeling and heart failure. Insufficient post-MI myocardial angiogenesis has been identified as a non-negligible event which precipitates heart failure progression. Previous studies reported that cytochrome P450 epoxygenase and its metabolites exerted beneficial effects on cardiovascular diseases. However, the role of cytochrome P450 2J2 (CYP2J2) in post-MI heart failure is incompletely understood. METHODS AND RESULTS: First, western blot and real-time PCR analyses showed that CYP2J2 expression increased clearly in patients with acute MI and old MI, compared to control. Second, echocardiography and histological studies showed that transgenic (TG) rats had relatively preserved cardiac function, as well as attenuated remodeling, and reduced scar formation, compared to the wild-type (WT) littermates after MI eight weeks. Importantly, the cardioprotective effect induced by CYP2J2 overexpression was abrogated by VEGFR2 inhibitor-cediranib. More intriguingly, positron emission computed Tomography (PET) analyses showed that TG rats displayed better myocardial perfusion than WT rats. We found that these effects were linked to increasing circulating EETs and enhancing myocardial angiogenesis. Additionally, in vitro study demonstrated that 11, 12-epoxyeicosatrienoic acid (11, 12-EET) induced more robust tube formation and markedly increased VEGF-A and bFGF expression in hypoxia and normoxia. Finally, western blot analyses uncovered that CYP2J2 and 11, 12-EET promoted angiogenesis via the Jagged1/Notch1 signaling pathway. CONCLUSIONS: Our findings demonstrate that CYP2J2 improves cardiac function by increasing the concentration of circulating EETs, and boosting angiogenesis via the Jagged1/Notch1 signaling pathway in MI-induced heart failure.
BACKGROUND:Myocardial infarction (MI) contributes to the development of cardiac remodeling and heart failure. Insufficient post-MI myocardial angiogenesis has been identified as a non-negligible event which precipitates heart failure progression. Previous studies reported that cytochrome P450 epoxygenase and its metabolites exerted beneficial effects on cardiovascular diseases. However, the role of cytochrome P450 2J2 (CYP2J2) in post-MI heart failure is incompletely understood. METHODS AND RESULTS: First, western blot and real-time PCR analyses showed that CYP2J2 expression increased clearly in patients with acute MI and old MI, compared to control. Second, echocardiography and histological studies showed that transgenic (TG) rats had relatively preserved cardiac function, as well as attenuated remodeling, and reduced scar formation, compared to the wild-type (WT) littermates after MI eight weeks. Importantly, the cardioprotective effect induced by CYP2J2 overexpression was abrogated by VEGFR2 inhibitor-cediranib. More intriguingly, positron emission computed Tomography (PET) analyses showed that TG rats displayed better myocardial perfusion than WT rats. We found that these effects were linked to increasing circulating EETs and enhancing myocardial angiogenesis. Additionally, in vitro study demonstrated that 11, 12-epoxyeicosatrienoic acid (11, 12-EET) induced more robust tube formation and markedly increased VEGF-A and bFGF expression in hypoxia and normoxia. Finally, western blot analyses uncovered that CYP2J2 and 11, 12-EET promoted angiogenesis via the Jagged1/Notch1 signaling pathway. CONCLUSIONS: Our findings demonstrate that CYP2J2 improves cardiac function by increasing the concentration of circulating EETs, and boosting angiogenesis via the Jagged1/Notch1 signaling pathway in MI-induced heart failure.
Authors: Rushendhiran Kesavan; Timo Frömel; Sven Zukunft; Bernhard Brüne; Andreas Weigert; Ilka Wittig; Rüdiger Popp; Ingrid Fleming Journal: Int J Mol Sci Date: 2021-07-01 Impact factor: 5.923