Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects
Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTP...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | Journal of Cardiovascular Development and Disease |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2308-3425/8/3/29 |
| _version_ | 1797541228363907072 |
|---|---|
| author | Carmen Leung Anish Engineer Mella Y. Kim Xiangru Lu Qingping Feng |
| author_facet | Carmen Leung Anish Engineer Mella Y. Kim Xiangru Lu Qingping Feng |
| author_sort | Carmen Leung |
| collection | DOAJ |
| description | Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase <i>Rac1</i> acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of <i>Rac1</i> in embryonic heart development. Methods and Results: The <i>Nkx2.5-Cre</i> transgenic mice were crossed with <i>Rac1<sup>f/f</sup></i> mice to generate mice with a cardiomyocyte specific deletion of <i>Rac1</i> (<i>Rac1<sup>Nkx2.5</sup></i>) during heart development. Embryonic <i>Rac1<sup>Nkx2.5</sup></i> hearts at E12.5–E18.5 were collected for histological analysis. Overall, <i>Rac1<sup>Nkx2.5</sup></i> hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. <i>Rac1<sup>Nkx2.5</sup></i> hearts also exhibited ventricular septal defects (VSDs) and double outlet right ventricle (DORV) or overriding aorta. Cardiomyocytes had a rounded morphology and were highly disorganized, and the myocardial expression of Scrib, a planar cell polarity protein, was reduced in <i>Rac1<sup>Nkx2.5</sup></i> hearts. In addition, cell proliferation rate was significantly decreased in the <i>Rac1<sup>Nkx2.5</sup></i> ventricular myocardium at E9.5. Conclusions: <i>Rac1</i> deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in <i>Rac1<sup>Nkx2.5</sup></i> hearts, implicating <i>Rac1</i> signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development. |
| first_indexed | 2024-03-10T13:13:13Z |
| format | Article |
| id | doaj.art-1e66db00280c4c2ebbef80895751e837 |
| institution | Directory Open Access Journal |
| issn | 2308-3425 |
| language | English |
| last_indexed | 2024-03-10T13:13:13Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Cardiovascular Development and Disease |
| spelling | doaj.art-1e66db00280c4c2ebbef80895751e8372023-11-21T10:33:48ZengMDPI AGJournal of Cardiovascular Development and Disease2308-34252021-03-01832910.3390/jcdd8030029Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract DefectsCarmen Leung0Anish Engineer1Mella Y. Kim2Xiangru Lu3Qingping Feng4Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaBackground: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase <i>Rac1</i> acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of <i>Rac1</i> in embryonic heart development. Methods and Results: The <i>Nkx2.5-Cre</i> transgenic mice were crossed with <i>Rac1<sup>f/f</sup></i> mice to generate mice with a cardiomyocyte specific deletion of <i>Rac1</i> (<i>Rac1<sup>Nkx2.5</sup></i>) during heart development. Embryonic <i>Rac1<sup>Nkx2.5</sup></i> hearts at E12.5–E18.5 were collected for histological analysis. Overall, <i>Rac1<sup>Nkx2.5</sup></i> hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. <i>Rac1<sup>Nkx2.5</sup></i> hearts also exhibited ventricular septal defects (VSDs) and double outlet right ventricle (DORV) or overriding aorta. Cardiomyocytes had a rounded morphology and were highly disorganized, and the myocardial expression of Scrib, a planar cell polarity protein, was reduced in <i>Rac1<sup>Nkx2.5</sup></i> hearts. In addition, cell proliferation rate was significantly decreased in the <i>Rac1<sup>Nkx2.5</sup></i> ventricular myocardium at E9.5. Conclusions: <i>Rac1</i> deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in <i>Rac1<sup>Nkx2.5</sup></i> hearts, implicating <i>Rac1</i> signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development.https://www.mdpi.com/2308-3425/8/3/29<i>Rac1</i>proliferationcell polaritycongenital heart defectscompact myocardiumtrabeculation |
| spellingShingle | Carmen Leung Anish Engineer Mella Y. Kim Xiangru Lu Qingping Feng Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects Journal of Cardiovascular Development and Disease <i>Rac1</i> proliferation cell polarity congenital heart defects compact myocardium trabeculation |
| title | Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects |
| title_full | Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects |
| title_fullStr | Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects |
| title_full_unstemmed | Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects |
| title_short | Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects |
| title_sort | myocardium specific deletion of rac1 causes ventricular noncompaction and outflow tract defects |
| topic | <i>Rac1</i> proliferation cell polarity congenital heart defects compact myocardium trabeculation |
| url | https://www.mdpi.com/2308-3425/8/3/29 |
| work_keys_str_mv | AT carmenleung myocardiumspecificdeletionofrac1causesventricularnoncompactionandoutflowtractdefects AT anishengineer myocardiumspecificdeletionofrac1causesventricularnoncompactionandoutflowtractdefects AT mellaykim myocardiumspecificdeletionofrac1causesventricularnoncompactionandoutflowtractdefects AT xiangrulu myocardiumspecificdeletionofrac1causesventricularnoncompactionandoutflowtractdefects AT qingpingfeng myocardiumspecificdeletionofrac1causesventricularnoncompactionandoutflowtractdefects |