Department of Pathophysiology, Oita University School of Medicine, Oita, Japan.
Department of Cardiovascular Medicine, Hebei Medical University, Shijiazhuang, Hebei, China.
J Physiol Sci. 2020 Sep 7;70(1):39. doi: 10.1186/s12576-020-00766-x.
Signal regulators during early cardiogenetic differentiation for the cellular automaticity are largely unknown. Our investigations were designed to clarify the role of transcription factors and their modulators in P19-derived cardiomyocytes to the expression of cardiac pacemaker ion channels. Transcription factors Csx/Nkx2.5 and GATA4 but not MEF2C were markedly inhibited by p38 MAP kinase inhibition in a distinct manner; expression but not phosphorylation of GATA4 was reduced by inhibition of p38 MAP kinase actions. In the presence of an ERK1/2,5 inhibitor PD98059 or a JNK MAP kinase inhibitor SP600125, P19 cells successfully differentiated into cardiomyocytes displaying spontaneous beatings with expression of three types of pacemaker ion channels. We demonstrate that acquisition of cellular automaticity and the expression of pacemaker ion channels are regulated by the transcription factors, Csx/Nkx2.5 and GATA4, through intracellular signals including p38 MAP kinase in the process of P19-derived pluripotent cells differentiation into cardiomyocytes.
在心脏发生早期的细胞自动性中，信号调节剂在很大程度上是未知的。我们的研究旨在阐明转录因子及其调节剂在 P19 衍生的心肌细胞中对心脏起搏离子通道表达的作用。转录因子 Csx/Nkx2.5 和 GATA4 而非 MEF2C 被 p38 MAP 激酶抑制剂以明显不同的方式显著抑制；p38 MAP 激酶作用的抑制减少了 GATA4 的表达而不是磷酸化。在 ERK1/2、5 抑制剂 PD98059 或 JNK MAP 激酶抑制剂 SP600125 的存在下，P19 细胞成功分化为具有三种起搏离子通道表达的自发搏动的心肌细胞。我们证明，细胞自动性的获得和起搏离子通道的表达是通过转录因子 Csx/Nkx2.5 和 GATA4 调节的，包括 p38 MAP 激酶在内的细胞内信号参与了 P19 多能细胞向心肌细胞分化的过程。
