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

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.