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Published on: April 15, 2020
Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism
Wuxia Gu1, Hongyan Li1, Wenjing Yuan1
1Department 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.
Abstract:
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.
Insights
Phosphodiesterase 4D interacting protein (PDE4DIP) contributes to left ventricular non-compaction (LVNC) by disrupting cell polarity, cytoskeleton, and energy metabolism via the Rho-ROCK pathway.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Left ventricular non-compaction (LVNC) is a hereditary cardiomyopathy with few treatment options.
- Previous research implicated phosphodiesterase 4D interacting protein (PDE4DIP) in LVNC development.
Purpose of the Study:
- To investigate the functional role of PDE4DIP in regulating cell polarity, cytoskeleton, and energy metabolism.
- To elucidate the molecular mechanisms by which PDE4DIP drives LVNC development.
Main Methods:
- Bioinformatics analysis of PDE4DIP expression in LVNC patients.
- In vitro studies involving PDE4DIP overexpression and knockdown in cardiomyocytes.
- Assessment of mitochondrial morphology and function, gene/protein expression, cell migration, and proliferation.
Main Results:
- PDE4DIP expression was elevated in LVNC-derived cardiomyocytes.
- PDE4DIP overexpression led to cytoskeletal disorganization, reduced ATP, decreased cell migration, and increased proliferation and mitochondrial vacuolation.
- PDE4DIP knockdown improved cytoskeleton formation, ATP content, and cell migration.
- PDE4DIP regulates cell polarity, cytoskeleton, and Rho-ROCK signaling.
Conclusions:
- PDE4DIP plays a critical role in LVNC pathogenesis.
- PDE4DIP influences LVNC by modulating cell polarity, cytoskeleton, and energy metabolism through the Rho-ROCK pathway.
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