Although
hypoxia induces aberrant gene expression and dedifferentiation of smooth muscle cells (SMCs), mechanisms that alter dedifferentiation gene expression by
hypoxia remain unclear. Therefore, we aimed to gain insight into the
hypoxia-controlled gene expression in SMCs. We conducted studies using SMCs cultured in 3%
oxygen (
hypoxia) and the lungs of mice exposed to 10%
oxygen (
hypoxia). Our results suggest
hypoxia upregulated expression of
transcription factor CP2-like protein1, krüppel-like factor 4, and
E2f transcription factor 1 enriched genes including basonuclin 2 (Bcn2),
serum response factor (Srf), polycomb 3 (Cbx8), homeobox D9 (Hoxd9),
lysine demethylase 1A (Kdm1a), etc. Additionally, we found that silencing
glucose-6-phosphate dehydrogenase (G6PD) expression and inhibiting G6PD activity downregulated Srf transcript and hypomethylation of SMC genes (Myocd, Myh11, and Cnn1) and concomitantly increased their expression in the lungs of hypoxic mice. Furthermore, G6PD inhibition hypomethylated MEG3, a
long non-coding RNA, gene and upregulated MEG3 expression in the lungs of hypoxic mice and in hypoxic SMCs. Silencing MEG3 expression in SMC mitigated the
hypoxia-induced transcription of SRF. These findings collectively demonstrate that MEG3 and G6PD codependently regulate Srf expression in hypoxic SMCs. Moreover, G6PD inhibition upregulated SRF-MYOCD-driven gene expression, determinant of a differentiated SMC phenotype.