Nkx2.5 insufficiency leads to atrial electrical remodeling through Wnt signaling in HL‑1 cells

Abstract

Homeobox protein Nxk-2.5 (Nkx2.5) is a homeobox transcription factor that promotes chamber-like myocardial gene expression. Data from a previous genome-wide association study suggested that Nkx2.5 may be associated with the genetic variation that underlies atrial fibrillation (AF). Nkx2.5 loss of function has been demonstrated to be associated with an increasing susceptibility of familial AF. Therefore, the aim of the present study was to investigate the effect of Nkx2.5 loss of function on electrophysiological substrates in HL-1 cells. To the best of our knowledge, the results demonstrated for the first time that Nkx2.5 expression was significantly decreased in a rat model exhibiting AF. The effect of silencing Nkx2.5 was assessed following transfection with adenoviral vectors with specific NKX2.5-shRNA. The effect of Nkx2.5 silencing on potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), gap junction alpha-5 protein (Cx40), calcium handling proteins and protein Wnt-11 (Wnt11) expression levels was also assessed in HL-1 cells. The results revealed that Nkx2.5 silencing increased HCN4 expression, decreased Cx40 expression and disrupted the expression of calcium handling proteins. Additionally, Wnt11 signal protein expression was decreased following Nkx2.5 silencing. The results of the present study demonstrated that Nkx2.5 served as a transcriptional regulator of the electrophysiological substrates associated with AF.

WNT signaling in atrial fibrillation

“…The homeobox transcription factor Nkx2.5 is implicated in heart development and growth and was shown to be associated with a genetic variation that underlies AF. 48 In HL-1 cardiomyocytes, silencing of Nkx2.5 resulted in decreased expression of Wnt11 49 which is in line with the crucial function of Wnt signaling in development.…”

D-galactose causes sinoatrial node dysfunction: from phenotype to mechanism

“…Studies have shown that Shox2-knockout mice died during pregnancy due to cardiac conduction system defects, including SAN and valve sinus hypoplasia accompanied the loss of T-box transcription factor 3 and HCN4 expression and ectopic natriuretic peptide A, connexin 40, and NKX2-5 expression in the SAN, which suggested that the differentiation of SAN failed in Shox2-knockout mice, and the cells in SAN area differentiated into working cardiomyocytes instead of P cells [29]. The regulation of SHOX2 on downstream BMP4, GATA4 and NKX2-5 is helpful to promote the expression of HCN4 and CAV3.1, which is of great significance for maintaining the pacing function of SAN and inhibiting the transformation of P cells into working cardiomyocytes [30][31][32][33].…”

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

“…Rats displayed a reduced level of Nkx2.5, particularly in the left atrium, after coronary artery ligation. Moreover, the RNA interference strategy was successful in decreasing NKX2.5 mRNA transcript and protein, enhancing the expression of HCN4 and almost silencing Cx40, SERCA, phospholamban, and Cav1.2, all proteins fundamental in Ca 2+ handling [278].…”