Transcriptomic Changes in Endothelial Cells Triggered by Na,K-ATPase Inhibition: A Search for Upstream Na(+)(i)/K(+)(i) Sensitive Genes

Stimulus-dependent elevation of intracellular Ca(2+) affects gene expression via well-documented calmodulin-mediated signaling pathways. Recently, we found that the addition of extra- and intracellular Ca(2+) chelators increased, rather than decreased, the number of genes expressed, and that this is affected by the elevation of [Na(+)](i)/[K(+)](i)-ratio. This assumes the existence of a novel Na(+)(i)/K(+)(i)-mediated Ca(2+)(i)-independent mechanism of excitation-transcription coupling. To identify upstream Na(+)(i)/K(+)(i)-sensitive genes, we examined the kinetics of transcriptomic changes in human umbilical vein endothelial cells (HUVEC) subjected to Na,K-ATPase inhibition by ouabain or K(+)-free medium. According to our data, microRNAs, transcription factors, and proteins involved in immune response and inflammation might be considered as key components of Na(+)(i)/K(+)(i)-mediated excitation-transcription coupling. Special attention was focused on the FOS gene and the possible mechanism of transcription regulation via G-quadruplexes, non-canonical secondary structures of nucleic acids, whose stability depends on [Na(+)](i)/[K(+)](i)-ratio. Verification of the [Na(+)](i)/[K(+)](i)-sensitive transcription regulation mechanism should be continued in forthcoming studies.