Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11
Background: Diabetic cardiomyopathy (DCM) is a prevalent and severe complication of diabetes, for which effective management strategies remain limited. Ubiquitin-specific protease 38 (USP38) has been associated with various cardiovascular diseases. In this study, we investigate the role of USP38 in...
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Elsevier
2025-07-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725002174 |
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| author | Zheng Xiao Yucheng Pan Hong Meng Zongze Qu Liang Guo Bin Kong Wei Shuai He Huang |
| author_facet | Zheng Xiao Yucheng Pan Hong Meng Zongze Qu Liang Guo Bin Kong Wei Shuai He Huang |
| author_sort | Zheng Xiao |
| collection | DOAJ |
| description | Background: Diabetic cardiomyopathy (DCM) is a prevalent and severe complication of diabetes, for which effective management strategies remain limited. Ubiquitin-specific protease 38 (USP38) has been associated with various cardiovascular diseases. In this study, we investigate the role of USP38 in the pathogenesis of DCM. Methods: Cardiomyocyte-specific transgenic and knockout USP38 mice were generated, and diabetic mouse model was established using streptozotocin injections. Neonatal rat cardiomyocytes exposed to high glucose conditions were utilized for in vitro experiments. Cardiac remodeling was assessed through echocardiography, electrophysiological analysis, histological assessment, and molecular analysis. Results: USP38 expression was significantly upregulated in DCM. Cardiomyocyte-specific USP38 overexpression aggravated cardiac dysfunction, cardiac inflammation and myocardial fibrosis, mitochondrial dysfunction, and increased vulnerability to ventricular arrhythmia in diabetic mice. Conversely, cardiomyocyte-specific USP38 deletion improved cardiac structural and electrical remodeling and attenuated mitochondrial impairment. Similar results were observed in vitro. Mechanistically, RNA-sequencing analysis, immunoprecipitation and mass spectrometry analysis and lipidomic analysis demonstrated that USP38 directly interacts with Acy-CoA dehydrogenase (ACAD11), deubiquitinating and inactivating it. This leads to abnormal fatty acid oxidation and subsequent activation of the receptor for advanced glycation end products (RAGE) pathway in diabetic heart. Pharmacological inhibition of RAGE using FPS-ZM1 hampered cardiac remodeling and dysfunction in cardiomyocyte-specific USP38 overexpressing diabetic mice. Conclusion: The study demonstrates that USP38 exacerbates diabetes-induced cardiac remodeling and DCM via post-translational modification of ACAD11, highlighting a novel therapeutic target for DCM. |
| format | Article |
| id | doaj-art-07a5e1296d474737ab8ee25948b47ac7 |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-07a5e1296d474737ab8ee25948b47ac72025-08-20T02:02:24ZengElsevierRedox Biology2213-23172025-07-018410370410.1016/j.redox.2025.103704Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11Zheng Xiao0Yucheng Pan1Hong Meng2Zongze Qu3Liang Guo4Bin Kong5Wei Shuai6He Huang7Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Corresponding author. Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei, China.Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Corresponding author. Department of Cardiology, Renmin Hospital of Wuhan University, 238 jiefang Road, Wuhan 430060, Hubei, China.Background: Diabetic cardiomyopathy (DCM) is a prevalent and severe complication of diabetes, for which effective management strategies remain limited. Ubiquitin-specific protease 38 (USP38) has been associated with various cardiovascular diseases. In this study, we investigate the role of USP38 in the pathogenesis of DCM. Methods: Cardiomyocyte-specific transgenic and knockout USP38 mice were generated, and diabetic mouse model was established using streptozotocin injections. Neonatal rat cardiomyocytes exposed to high glucose conditions were utilized for in vitro experiments. Cardiac remodeling was assessed through echocardiography, electrophysiological analysis, histological assessment, and molecular analysis. Results: USP38 expression was significantly upregulated in DCM. Cardiomyocyte-specific USP38 overexpression aggravated cardiac dysfunction, cardiac inflammation and myocardial fibrosis, mitochondrial dysfunction, and increased vulnerability to ventricular arrhythmia in diabetic mice. Conversely, cardiomyocyte-specific USP38 deletion improved cardiac structural and electrical remodeling and attenuated mitochondrial impairment. Similar results were observed in vitro. Mechanistically, RNA-sequencing analysis, immunoprecipitation and mass spectrometry analysis and lipidomic analysis demonstrated that USP38 directly interacts with Acy-CoA dehydrogenase (ACAD11), deubiquitinating and inactivating it. This leads to abnormal fatty acid oxidation and subsequent activation of the receptor for advanced glycation end products (RAGE) pathway in diabetic heart. Pharmacological inhibition of RAGE using FPS-ZM1 hampered cardiac remodeling and dysfunction in cardiomyocyte-specific USP38 overexpressing diabetic mice. Conclusion: The study demonstrates that USP38 exacerbates diabetes-induced cardiac remodeling and DCM via post-translational modification of ACAD11, highlighting a novel therapeutic target for DCM.http://www.sciencedirect.com/science/article/pii/S2213231725002174Diabetic cardiomyopathyUbiquitin-specific protease 38Mitochondrial dysfunctionAcyl-CoA dehydrogenase 11Receptors of advanced glycemic end products |
| spellingShingle | Zheng Xiao Yucheng Pan Hong Meng Zongze Qu Liang Guo Bin Kong Wei Shuai He Huang Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11 Redox Biology Diabetic cardiomyopathy Ubiquitin-specific protease 38 Mitochondrial dysfunction Acyl-CoA dehydrogenase 11 Receptors of advanced glycemic end products |
| title | Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11 |
| title_full | Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11 |
| title_fullStr | Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11 |
| title_full_unstemmed | Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11 |
| title_short | Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11 |
| title_sort | ubiquitin specific protease 38 exacerbates diabetic cardiomyopathy via post translational modification of acad11 |
| topic | Diabetic cardiomyopathy Ubiquitin-specific protease 38 Mitochondrial dysfunction Acyl-CoA dehydrogenase 11 Receptors of advanced glycemic end products |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725002174 |
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