Transcriptomic Changes in Endothelial Cells Triggered by Na,K-ATPase Inhibition: A Search for Upstream Na⁺_i/K⁺_i...

Stimulus-dependent elevation of intracellular Ca²⁺ affects gene expression via well-documented calmodulin-mediated signaling pathways. Recently, we found that the addition of extra- and intracellular Ca²⁺ 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 Ca²⁺_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.