Abstract
Hypoxia-inducible factor-1 (HIF-1) regulates the expression of hypoxia-inducible genes by binding erythropoietin (EPO) enhancer fragments. Of these genes, HIF-1 upregulates voltage-gated K+1.2 channels (Kv1.2) in rat PC12 cells. Whether HIF-1 regulates hypoxia-induced Kv channel expression in cultured pulmonary artery smooth muscle cells (PASMCs), however, has not been determined. In this study, we investigated the effects of hypoxia on the expression of Kv1.2 Kv1.5, Kv2.1, and Kv9.3 channels in PASMCs and examined the direct role of HIF-1 by transfecting either wild type or mutant EPO enhancer fragments. Our results showed that 18 h exposure to hypoxia significantly increased the expression of Kv1.2, Kv1.5, Kv2.1, and Kv9.3; and this hypoxia-induced upregulation was completely inhibited after transfection with the wild type but not mutant EPO enhancer fragment. These results indicate that HIF-1 regulates hypoxia-stimulated induction of Kv1.2 Kv1.5, Kv2.1, and Kv9.3 channels in cultured PASMCs.
Highlights
Efficient gas exchange in the lungs is maintained through a mechanism known as hypoxic pulmonary vasoconstriction (HPV), which serves to match local perfusion to ventilation and optimize arterial blood gas exchange
The goals of this study were to evaluate the effects of hypoxia on Kv α subunit expression in pulmonary artery smooth muscle cells (PASMCs) and to determine the role of the EPO enhancer element on
H hypoxia exposure increased the expression of PASMC Kv α subunits (Kv . , Kv . , Kv . , and Kv . ) at the transcriptional level; (b) protein expression of Kv . , Kv . , and Kv . channels were significantly increased after h hypoxia and (c) the effects of h hypoxia were completely blocked following transfection with wild type but not mutant EPO-enhancer fragment
Summary
Efficient gas exchange in the lungs is maintained through a mechanism known as hypoxic pulmonary vasoconstriction (HPV), which serves to match local perfusion to ventilation and optimize arterial blood gas exchange. Hypoxia has recently been shown to induce pulmonary artery contraction, even after the endothelium has been denuded [ , ]. This hypoxia-induced constriction has been demonstrated to occur by inhibition of voltage-gated potassium channels (Kv) at the single pulmonary artery smooth muscle cell level. There have been few studies on how shorter hypoxia exposures alter the mRNA and protein expression of these particular Kv α subunits QIAN DONG ET AL.: HYPOXIA INDUCES VOLTAGE GATED K+ KV CHANNEL EXPRESSION IN PULMONARY ARTERIAL SMOOTH MUSCLE CELLS THROUGH HYPOXIA INDUCIBLE FACTOR 1 HIF 1. Transient transfection with either wild or mutant EPO ’-enhancer fragments was used to determine the role of HIF- and reveal HPV-dependent molecular mechanisms
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