Left ventricular non-compaction (LVNC), a genetically inherited myocardial disorder, is the third most common cardiomyopathy, with limited treatment options. Recent evidence has implicated cytoskeleton-related genes in the development of LVNC; however, the mechanisms driving LVNC pathogenesis remain poorly understood.
In this study, published in the Genes & Diseases journal, researchers at Children's Hospital of Chongqing Medical University, Chongqing Medical University, and Washington University School of Medicine in St. Louis elucidate the critical role of PDE4DIP in the development of LVNC.
In their previous study, the authors had identified that phosphodiesterase 4D interacting protein (PDE4DIP) is associated with LVNC development. In the current study, the authors aimed to elucidate the functional role of PDE4DIP activation in regulating cell polarity, cytoskeleton, and energy metabolism, as well as the mechanisms driving LVNC development.
The authors isolated human-induced pluripotent stem cells (hiPSCs) from LVNC and normal patients and successfully induced them into cardiomyocytes (hiPSC-CMs). TEM and gene ontology analysis of these cells revealed that disruption of cell polarity, cytoskeleton, and energy metabolism are the key cellular alterations underlying LVNC pathogenesis. Further experiments identified PDE4DIP as an LVNC pathogenic gene, the overexpression of which lowers metabolism, decreases the expression of several cytoskeleton-related proteins and genes, and reduces the expression of polarity-related proteins and genes, ultimately leading to the development of LVNC. Knockdown of PDE4DIP improves cell polarity, skeleton, and energy release, both in vitro and in vivo.
Overexpression of PDE4DIP reduces the expression of RhoA, an upstream protein in the Rho/ROCK pathway. The Rho/ROCK pathway is essential for cell growth, migration, adhesion, and cytoskeletal organization. PDE4DIP-mediated RhoA repression, along with a concomitant increase in CDC42, results in a decrease in the cell's ability to form polarity and skeleton.
In conclusion, this study not only provides key insights into how PDE4DIP regulates cell polarity, the cytoskeleton, and energy metabolism via the Rho-ROCK pathway during LVNC pathogenesis but also offers fresh perspectives into potential targets and therapeutic strategies against LVNC.
Reference
Title of the original paper: Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101568
