Abstract
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 Rac1 acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of Rac1 in embryonic heart development. Methods and Results: The Nkx2.5-Cre transgenic mice were crossed with Rac1f/f mice to generate mice with a cardiomyocyte specific deletion of Rac1 (Rac1Nkx2.5) during heart development. Embryonic Rac1Nkx2.5 hearts at E12.5–E18.5 were collected for histological analysis. Overall, Rac1Nkx2.5 hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. Rac1Nkx2.5 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 Rac1Nkx2.5 hearts. In addition, cell proliferation rate was significantly decreased in the Rac1Nkx2.5 ventricular myocardium at E9.5. Conclusions: Rac1 deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in Rac1Nkx2.5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development.
Highlights
Congenital heart defects (CHDs) are the most common human birth defects, affecting up to 5% of live births [1,2]
We show that Rac1 signaling is crucial for ventricular myocardium development and cardiomyocyte specific deficiency of Rac1 leads to a spectrum of CHDs including a thin compact myocardium and hypertrabeculation, similar to clinical features of Left ventricular noncompaction (LVNC)
The Rac1 mRNA expression was significantly decreased by approximately 35% in Rac1Nkx2.5 ventricular myocardium compared to littermate Rac1f/f controls (Figure 1C)
Summary
Congenital heart defects (CHDs) are the most common human birth defects, affecting up to 5% of live births [1,2]. Noncompaction of the ventricular myocardium can increase the risk of cardiac embolism, atrial fibrillation, ventricular arrhythmia and heart failure [5,7]. This defect occurs mostly in the LV, right ventricular (RV) noncompaction has been reported in less than one-half of LVNC patients [8,9]. Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. A spectrum of CHDs arises in Rac1Nkx2.5 hearts, implicating Rac signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development
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