Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis
Abstract Aims Diabetic cardiomyopathy (DC) is one of serious complications of diabetic patients. This study investigated the biological function of activating transcription factor 4 (ATF4) in DC. Methods and results Streptozotocin‐treated mice and high glucose (HG)‐exposed HL‐1 cells were used as th...
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Wiley
2023-08-01
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Series: | ESC Heart Failure |
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Online Access: | https://doi.org/10.1002/ehf2.14404 |
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author | Yu Li Qian He Chao‐Yong He Chao Cai Zhen Chen Jing‐Zhu Duan |
author_facet | Yu Li Qian He Chao‐Yong He Chao Cai Zhen Chen Jing‐Zhu Duan |
author_sort | Yu Li |
collection | DOAJ |
description | Abstract Aims Diabetic cardiomyopathy (DC) is one of serious complications of diabetic patients. This study investigated the biological function of activating transcription factor 4 (ATF4) in DC. Methods and results Streptozotocin‐treated mice and high glucose (HG)‐exposed HL‐1 cells were used as the in vivo and in vitro models of DC. Myocardial infarction (MI) was induced by left coronary artery ligation in mice. Cardiac functional parameters were detected by echocardiography. Target molecule expression was determined by real time quantitative PCR and western blotting. Cardiac fibrosis was observed by haematoxylin and eosin and Masson's staining. Cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelling. Activities of superoxide dismutase, glutathione peroxidase, and levels of malonic dialdehyde and reactive oxygen species were used to assess oxidative stress damage. Molecular mechanisms were evaluated by chromatin immunoprecipitation, dual luciferase assay, and co‐immunoprecipitation. ATF4 was up‐regulated in the DC and MI mice (P < 0.01). Down‐regulation of ATF4 improved cardiac function as evidenced by changes in cardiac functional parameters (P < 0.01), inhibited myocardial collagen I (P < 0.001) and collagen III (P < 0.001) expression, apoptosis (P < 0.001), and oxidative stress (P < 0.001) in diabetic mice. Collagen I (P < 0.01) and collagen III (P < 0.01) expression was increased in MI mice, which was reversed by ATF4 silencing (P < 0.05). ATF4 depletion enhanced viability (P < 0.01), repressed apoptosis (P < 0.001), oxidative damage (P < 0.001), and collagen I (P < 0.001), and collagen III (P < 0.001) expression of HG‐stimulated HL‐1 cells. ATF4 transcriptionally activated Smad ubiquitin regulatory factor 2 (Smurf2, P < 0.001) to promote ubiquitination and degradation of homeodomain interacting protein kinase‐2 (P < 0.001) and subsequently caused inactivation of nuclear factor erythroid 2‐related factor 2/heme oxygenase 1 pathway (P < 0.001). The inhibitory effects of ATF4 silencing on HG‐induced apoptosis (P < 0.01), oxidative injury (P < 0.01), collagen I (P < 0.001), and collagen III (P < 0.001) expression were reversed by Smurf2 overexpression. Conclusions ATF4 facilitates diabetic cardiac fibrosis and oxidative stress by promoting Smurf2‐mediated ubiquitination and degradation of homeodomain interacting protein kinase‐2 and then inactivation of nuclear factor erythroid 2‐related factor 2/heme oxygenase 1 pathway, suggesting ATF4 as a treatment target for DC. |
first_indexed | 2024-03-12T21:26:27Z |
format | Article |
id | doaj.art-54192b188e854b3d81cc46966f771a75 |
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language | English |
last_indexed | 2024-03-12T21:26:27Z |
publishDate | 2023-08-01 |
publisher | Wiley |
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series | ESC Heart Failure |
spelling | doaj.art-54192b188e854b3d81cc46966f771a752023-07-28T06:30:48ZengWileyESC Heart Failure2055-58222023-08-011042510252310.1002/ehf2.14404Activating transcription factor 4 drives the progression of diabetic cardiac fibrosisYu Li0Qian He1Chao‐Yong He2Chao Cai3Zhen Chen4Jing‐Zhu Duan5Department of Cardiology Shiyan Taihe Hospital (Hubei University of Medicine) Shiyan ChinaDepartment of Cardiology Shiyan Taihe Hospital (Hubei University of Medicine) Shiyan ChinaDepartment of Cardiology Shiyan Taihe Hospital (Hubei University of Medicine) Shiyan ChinaDepartment of Cardiology Shiyan Taihe Hospital (Hubei University of Medicine) Shiyan ChinaDepartment of Cardiology Shiyan Taihe Hospital (Hubei University of Medicine) Shiyan ChinaDepartment of Respiratory Shiyan Taihe Hospital (Hubei University of Medicine) Shiyan ChinaAbstract Aims Diabetic cardiomyopathy (DC) is one of serious complications of diabetic patients. This study investigated the biological function of activating transcription factor 4 (ATF4) in DC. Methods and results Streptozotocin‐treated mice and high glucose (HG)‐exposed HL‐1 cells were used as the in vivo and in vitro models of DC. Myocardial infarction (MI) was induced by left coronary artery ligation in mice. Cardiac functional parameters were detected by echocardiography. Target molecule expression was determined by real time quantitative PCR and western blotting. Cardiac fibrosis was observed by haematoxylin and eosin and Masson's staining. Cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelling. Activities of superoxide dismutase, glutathione peroxidase, and levels of malonic dialdehyde and reactive oxygen species were used to assess oxidative stress damage. Molecular mechanisms were evaluated by chromatin immunoprecipitation, dual luciferase assay, and co‐immunoprecipitation. ATF4 was up‐regulated in the DC and MI mice (P < 0.01). Down‐regulation of ATF4 improved cardiac function as evidenced by changes in cardiac functional parameters (P < 0.01), inhibited myocardial collagen I (P < 0.001) and collagen III (P < 0.001) expression, apoptosis (P < 0.001), and oxidative stress (P < 0.001) in diabetic mice. Collagen I (P < 0.01) and collagen III (P < 0.01) expression was increased in MI mice, which was reversed by ATF4 silencing (P < 0.05). ATF4 depletion enhanced viability (P < 0.01), repressed apoptosis (P < 0.001), oxidative damage (P < 0.001), and collagen I (P < 0.001), and collagen III (P < 0.001) expression of HG‐stimulated HL‐1 cells. ATF4 transcriptionally activated Smad ubiquitin regulatory factor 2 (Smurf2, P < 0.001) to promote ubiquitination and degradation of homeodomain interacting protein kinase‐2 (P < 0.001) and subsequently caused inactivation of nuclear factor erythroid 2‐related factor 2/heme oxygenase 1 pathway (P < 0.001). The inhibitory effects of ATF4 silencing on HG‐induced apoptosis (P < 0.01), oxidative injury (P < 0.01), collagen I (P < 0.001), and collagen III (P < 0.001) expression were reversed by Smurf2 overexpression. Conclusions ATF4 facilitates diabetic cardiac fibrosis and oxidative stress by promoting Smurf2‐mediated ubiquitination and degradation of homeodomain interacting protein kinase‐2 and then inactivation of nuclear factor erythroid 2‐related factor 2/heme oxygenase 1 pathway, suggesting ATF4 as a treatment target for DC.https://doi.org/10.1002/ehf2.14404ATF4Diabetic cardiomyopathyFibrosisHIPK2Oxidative stressSmurf2 |
spellingShingle | Yu Li Qian He Chao‐Yong He Chao Cai Zhen Chen Jing‐Zhu Duan Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis ESC Heart Failure ATF4 Diabetic cardiomyopathy Fibrosis HIPK2 Oxidative stress Smurf2 |
title | Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis |
title_full | Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis |
title_fullStr | Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis |
title_full_unstemmed | Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis |
title_short | Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis |
title_sort | activating transcription factor 4 drives the progression of diabetic cardiac fibrosis |
topic | ATF4 Diabetic cardiomyopathy Fibrosis HIPK2 Oxidative stress Smurf2 |
url | https://doi.org/10.1002/ehf2.14404 |
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