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Keywords:

  • hypoxia;
  • miR-210;
  • MKP-1;
  • pulmonary hypertension

Abstract

Chonic hypoxia, smooth muscle cell (SMC) proliferation and vascular remodeling are hallmark features of pathogenic pulmonary artery hypertension. MicroRNAs (miRNAs), endogenously expressed small noncoding RNAs, regulate gene expression at the post-transcriptional level. MiR-210 is considered a “master miRNA” in the control of diverse functions in hypoxic cells and tissues and has a cytoprotective function in pulmonary artery SMCs during hypoxic stress. MiR-210 is also upregulated in lung tissue of chonically hypoxic mice suffering from pulmonary hypertension. Jin et al. (2010) showed that mice deficient in mitogen-activated protein kinase phosphatase 1 (MKP-1) had severe hypoxia-induced pulmonary hypertension, so MKP-1 may be important in the progression of hypoxic pulmonary artery hypertension. We investigated the possible interactions between miR-210 and MKP-1 and the effect on cell proliferation in hypoxic human pulmonary artery SMCs (hPASMCs). miR-210 was significantly increased in cultured hPASMCs exposed to 1% O2 hypoxia for 48 h, as was MKP-1 mRNA and protein expression. Furthermore, inhibiting miR-210 expression increased MKP-1 mRNA and protein expression in hPASMCs and decreased cell proliferation under hypoxia. Conversely, overexpressing miR-210 prevented hypoxia-induced MKP-1 expression with no effect on cell proliferation. siRNA knockdown of MKP-1 abolished the miR-210-inhibition prevention of cell proliferation under hypoxia. MKP-1 is a target of miR-210 and could mediate the negative regulation of miR-210 inhibition on hypoxic hPASMCs.