Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System

Abstract

A bout 0.9% of human neonates are born with congenital heart disease (CHD). CHD can arise from genetic and epigenetic abnormalities that affect the tight control of specification, proliferation, and migration of cardiac progenitors/myocytes.1,2 During cardiogenesis, cardiac progenitors/myocytes proliferate in two waves: primitive heart tube shows highest proliferative activity at arterial and venous poles where latemigrating second heart field progenitors are recruited. 3,4 Then, after the completion of looping, the working myocytes reinitiate mitotic activity, resulting in the ballooning of chambers at late gestational stages. 3,5 Non-ballooning regions, mainly mediastinal myocardium, 6,7 are distinct from appendage myocardium in their morphology, expression profile, 8 and ionic currents. Nkx2-5 is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages, from the early committed cardiac progenitors through the adult cardiomyocytes, and plays a pivotal role in the regulation of cardiac, vascular, and hematopoietic lineages. 4,[10][11][12][13][14][15] Human heterozygous mutations of NKX2-5 are associated with a spectrum of CHDs including septal defects, conotruncal malformations, hypoplastic left heart, and atrioventricular (AV) conduction block. In agreement with observations in patients, mouse genetics has revealed the complexity of the role of Nkx2-5. [16][17][18][19] Germline deletion of Nkx2-5 gene results in cardiac lethality at the early stages with defects in the myocardial wall thickening, trabeculation, and endocardial cushion formation, suggesting a pro-mitotic role of Nkx2-5. 4,12,13 Recent studies have shown that Nkx2-5 also plays a critical role at chamber ballooning stages. 3,5 Mutant mouse models with genetic deficiency or dysfunction of Nkx2-5 after midgestational stages lead to atrial septal defect (ASD) and conduction defects. [20][21][22][23][24] Despite common phenotypes, however, these studies show partially inconsistent results as to cardiomyocyte growth. Although the temporary controlled global deletion of Nkx2-5 after midgestational stage results in thin hypomorphic ventricle, 24 ventricular-specific deletion of Nkx2-5 shows hypertrophic ventricle with hypertrabeculation. 22 These apparently conflicting results can be, in part, due to the differential regulation of physiological cardiac growth in spatiotemporarily Rationale: Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart.Although human mutation of NKX2-5 is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused controversy as to whether Nkx2-5 regulates cardiomyocyte proliferation. diverse cardiac subpopulation. In addition, the secondary effect by altered pump function in Nkx2-5 mutants may be another factor that complicates the interpretation of the phenotypes of mouse models mentioned above. In fact, hemodynamics by itself is known to be an indepen...

Wnt11 regulates cardiac chamber development and disease during perinatal maturation

“…Echocardiography. To evaluate cardiac function of neonatal pups, a Vevo2100 high-frequency probe (30/45 MHz, Visual Sonics) was used as previously described (49,50). Briefly, ultrasound images were obtained in the transverse and sagittal planes for each pup.…”

Heterozygous deletion of sarcolipin maintains normal cardiac function

“…Thus, SLN downregulation may enhance atrial contractile function and remodeling. However, previous studies have suggested that there is no significant phenotype in heterozygous SLN KO mice (3,11,26), whereas limited data are available on the effect of the heterozygous SLN deletion. The present study demonstrated that SLN heterozygous deletion showed neither a molecular nor physiological cardiac phenotype at baseline.…”

“…1). Several studies have already verified the usefulness of Sln Cre/ϩ mice to understand the mechanisms of heart development and cardiac function using deletion of the gene of interest from the atrium (11,25,26).…”

Nkx2-5 Mutations in Patients With Nonsyndromic Congenital Heart Disease

“…Moreover, CHD is correlated with structural and numeral chromosomal abnormalities (12% -14%), like 21, 13 and 18 trisomy, turner, etc. [3,[5][6][7]. Congenital heart diseases also may be caused in result of defect in different parts of heart [3].…”