Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects

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.

Bifid cardiac apex and spongiform cardiomyopathy in fetus with small microdeletion 16p12.2 of paternal origin. Critical points in family communication on 16p12.2 microdeletion

“…Rac1 deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in Rac1 Nkx2.5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT (outflow tracts) alignment, along with compact myocardium growth and development 5 …”

“…5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT (outflow tracts) alignment, along with compact myocardium growth and development. 5 Human pathologies related to mutations of the two genes OTOA and UQCRC2 do not lead to cardiac anomalies. However, given the function of the proteins encoded by the two genes, it is possible that, in a particular genetic context, the absence of these proteins could give anomalies in the organization of the myocardium such as that found in our case.…”

“…A spectrum of CHDs arises in Rac1 Nkx2. 5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT (outflow tracts) alignment, along with compact myocardium growth and development. 5 Human pathologies related to mutations of the two genes OTOA and UQCRC2 do not lead to cardiac anomalies.…”

“…Another element of interest is the particular type of cardiomyopathy found on histopathological examination: heart with bifid apex and noncompact appearance of myocardium 5,6 …”

“…4 Another element of interest is the particular type of cardiomyopathy found on histopathological examination: heart with bifid apex and noncompact appearance of myocardium. 5,6 The malformed fetus was the first nonabortive pregnancy of clinically healthy and nonconsanguineous Italian parents after four spontaneous abortions in first trimester. The familial anamnesis was negative for genetic disease and malformative syndromes.…”