Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway
Left ventricular non-compaction (LVNC), is a hereditary cardiomyopathy with limited treatments. Our previous study linked phosphodiesterase 4D interacting protein (PDE4DIP) to LVNC development. To explore the functional role of PDE4DIP activation in regulating cell polarity, skeleton, and energy met...
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KeAi Communications Co., Ltd.
2025-09-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304225000571 |
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| author | Wuxia Gu Hongyan Li Wenjing Yuan Xiaoqiong Fu Rui Wang Xiaohui Xu Xuemei Liao LingJuan Liu Bo Pan Jie Tian Haixin Yuan Yi Huang Tiewei Lu |
| author_facet | Wuxia Gu Hongyan Li Wenjing Yuan Xiaoqiong Fu Rui Wang Xiaohui Xu Xuemei Liao LingJuan Liu Bo Pan Jie Tian Haixin Yuan Yi Huang Tiewei Lu |
| author_sort | Wuxia Gu |
| collection | DOAJ |
| description | Left ventricular non-compaction (LVNC), is a hereditary cardiomyopathy with limited treatments. Our previous study linked phosphodiesterase 4D interacting protein (PDE4DIP) to LVNC development. To explore the functional role of PDE4DIP activation in regulating cell polarity, skeleton, and energy metabolism, and to elucidate its mechanisms driving LVNC development, bioinformatics analysis was performed to compare its expression in LVNC patients and normal subjects. Overexpression and knockdown of PDE4DIP were constructed in H9C2 cells and neonatal Sprague–Dawley rat primary cardiomyocytes, respectively. Electron microscopy, MitoTracker-Green staining, and an ATP kit were employed to assess mitochondria's morphology and functional status. Real-time quantitative PCR, western blotting, and immunofluorescence assays were employed to detect the expression of cell polarity-, skeleton-, and Rho-ROCK signaling-related genes and proteins. Cell scratching and CCK-8 assays were employed to detect cell migration and proliferation abilities of H9C2, respectively. We found that PDE4DIP expression was increased in the LVNC-derived human-induced pluripotent stem cell-derived cardiomyocytes compared with normal subjects. Furthermore, overexpression of PDE4DIP induced cytoskeletal disorganization, decreased ATP content and cell migration, and increased cell proliferation and mitochondrial vacuolation. Moreover, the knockdown of PDE4DIP promoted cytoskeleton formation and contributed to increased ATP content and elevated cell migration. Mechanically, overexpression of PDE4DIP inhibited cell polarity-, skeleton-, and Rho-ROCK signaling-related genes and proteins, which could be increased by knockdown of PDE4DIP, suggesting that a critical regulation of PDE4DIP to Rho-ROCK pathway. This discovery suggests that PDE4DIP contributes to the development of LVNC by regulating cell polarity, skeleton, and energy metabolism through the Rho-ROCK pathway. |
| format | Article |
| id | doaj-art-949191ddfd7d4ee3be7dc284806d4653 |
| institution | DOAJ |
| issn | 2352-3042 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | KeAi Communications Co., Ltd. |
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| series | Genes and Diseases |
| spelling | doaj-art-949191ddfd7d4ee3be7dc284806d46532025-08-20T03:15:02ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422025-09-0112510156810.1016/j.gendis.2025.101568Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathwayWuxia Gu0Hongyan Li1Wenjing Yuan2Xiaoqiong Fu3Rui Wang4Xiaohui Xu5Xuemei Liao6LingJuan Liu7Bo Pan8Jie Tian9Haixin Yuan10Yi Huang11Tiewei Lu12Department of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, ChinaDepartment of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, ChinaDepartment of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, ChinaCenter for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China; Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USADepartment of Cardiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Key Cardiovascular Specialty, Key Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China; Corresponding author.Left ventricular non-compaction (LVNC), is a hereditary cardiomyopathy with limited treatments. Our previous study linked phosphodiesterase 4D interacting protein (PDE4DIP) to LVNC development. To explore the functional role of PDE4DIP activation in regulating cell polarity, skeleton, and energy metabolism, and to elucidate its mechanisms driving LVNC development, bioinformatics analysis was performed to compare its expression in LVNC patients and normal subjects. Overexpression and knockdown of PDE4DIP were constructed in H9C2 cells and neonatal Sprague–Dawley rat primary cardiomyocytes, respectively. Electron microscopy, MitoTracker-Green staining, and an ATP kit were employed to assess mitochondria's morphology and functional status. Real-time quantitative PCR, western blotting, and immunofluorescence assays were employed to detect the expression of cell polarity-, skeleton-, and Rho-ROCK signaling-related genes and proteins. Cell scratching and CCK-8 assays were employed to detect cell migration and proliferation abilities of H9C2, respectively. We found that PDE4DIP expression was increased in the LVNC-derived human-induced pluripotent stem cell-derived cardiomyocytes compared with normal subjects. Furthermore, overexpression of PDE4DIP induced cytoskeletal disorganization, decreased ATP content and cell migration, and increased cell proliferation and mitochondrial vacuolation. Moreover, the knockdown of PDE4DIP promoted cytoskeleton formation and contributed to increased ATP content and elevated cell migration. Mechanically, overexpression of PDE4DIP inhibited cell polarity-, skeleton-, and Rho-ROCK signaling-related genes and proteins, which could be increased by knockdown of PDE4DIP, suggesting that a critical regulation of PDE4DIP to Rho-ROCK pathway. This discovery suggests that PDE4DIP contributes to the development of LVNC by regulating cell polarity, skeleton, and energy metabolism through the Rho-ROCK pathway.http://www.sciencedirect.com/science/article/pii/S2352304225000571Cell polarityCytoskeletonLeft ventricular non-compactionMitochondriaPDE4DIPRho-ROCK |
| spellingShingle | Wuxia Gu Hongyan Li Wenjing Yuan Xiaoqiong Fu Rui Wang Xiaohui Xu Xuemei Liao LingJuan Liu Bo Pan Jie Tian Haixin Yuan Yi Huang Tiewei Lu Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway Genes and Diseases Cell polarity Cytoskeleton Left ventricular non-compaction Mitochondria PDE4DIP Rho-ROCK |
| title | Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway |
| title_full | Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway |
| title_fullStr | Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway |
| title_full_unstemmed | Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway |
| title_short | Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway |
| title_sort | dysfunction of pde4dip contributes to lvnc development by regulating cell polarity skeleton and energy metabolism via rho rock pathway |
| topic | Cell polarity Cytoskeleton Left ventricular non-compaction Mitochondria PDE4DIP Rho-ROCK |
| url | http://www.sciencedirect.com/science/article/pii/S2352304225000571 |
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