Inhibition of Kir2.1 channel-induced depolarization promotes cell biological activity and differentiation by modulating autophagy in late endothelial progenitor cells.
Other Scholarly Work
Zhang, Xiaoyun, Cui, Xiaodong, Li, Xin et al. (2019). Inhibition of Kir2.1 channel-induced depolarization promotes cell biological activity and differentiation by modulating autophagy in late endothelial progenitor cells.
. 127 57-66. 10.1016/j.yjmcc.2018.11.005
Endothelial progenitor cells (EPCs) play a crucial role in postnatal angiogenesis and neovascularization. Inward rectifier potassium channel 2.1 (Kir2.1) have been identified in EPCs. However, the effect of Kir2.1 on EPC function is not known. Here, we try to establish the role of Kir2.1 channels in EPC function and to provide first insights into the mechanisms.
Methods and results
We first observed that the expression of Kir2.1 gradually decreased with the differentiation of EPCs into ECs in gene and protein levels. Treatment with the Kir2.1-selective inhibitor ML133 or knockdown of Kir2.1 by shRNA triggered EPC depolarization and promoted EPC biological functions, such as migration, adhesion, angiogenesis and differentiation into ECs in vitro. Transplantation of ML133-treated or Kir2.1 knockdown EPCs facilitated re-endothelialization in the rat injured arterial segment and inhibited neointima formation in vivo. In parallel, ML133 significantly enhanced autophagy and autophagic flux. After suppression of autophagy by 3-methyladenine (3-MA), the effects of ML133 on in vitro function and in vivo endothelialization capacity of EPCs were significantly inhibited. Mechanistically, ML133-induced autophagy was mediated at least partly by increased the activity of reactive oxygen species (ROS) that likely through intracellular calcium.
Conclusion
Our study indicates that blocking or knockdown Kir2.1 results in a moderate depolarization of EPCs, which directly participated in enhancing EPC functions both in vitro and in vivo. In the mean time, autophagy signaling pathway is, at least in part, involved in this process. It may provide a potential target for the treatment or prevention of vascular injury and disease.
