| First Author | Wang CC | Year | 2018 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 315 |
| Issue | 3 | Pages | L422-L431 |
| PubMed ID | 29745253 | Mgi Jnum | J:267171 |
| Mgi Id | MGI:6199409 | Doi | 10.1152/ajplung.00475.2017 |
| Citation | Wang CC, et al. (2018) Pulmonary artery smooth muscle cell HIF-1alpha regulates endothelin expression via microRNA-543. Am J Physiol Lung Cell Mol Physiol 315(3):L422-L431 |
| abstractText | Pulmonary artery smooth muscle cells (PASMCs) express endothelin (ET-1), which modulates the pulmonary vascular response to hypoxia. Although cross-talk between hypoxia-inducible factor-1alpha (HIF-1alpha), an O2-sensitive transcription factor, and ET-1 is established, the cell-specific relationship between HIF-1alpha and ET-1 expression remains incompletely understood. We tested the hypotheses that in PASMCs 1) HIF-1alpha expression constrains ET-1 expression, and 2) a specific microRNA (miRNA) links HIF-1alpha and ET-1 expression. In human (h)PASMCs, depletion of HIF-1alpha with siRNA increased ET-1 expression at both the mRNA and protein levels ( P < 0.01). In HIF-1alpha(-/-) murine PASMCs, ET-1 gene and protein expression was increased ( P < 0.0001) compared with HIF-1alpha(+/+) cells. miRNA profiles were screened in hPASMCs transfected with siRNA-HIF-1alpha, and RNA hybridization was performed on the Agilent (Santa Clara, CA) human miRNA microarray. With HIF-1alpha depletion, miRNA-543 increased 2.4-fold ( P < 0.01). In hPASMCs, miRNA-543 overexpression increased ET-1 gene ( P < 0.01) and protein ( P < 0.01) expression, decreased TWIST gene expression ( P < 0.05), and increased ET-1 gene and protein expression, compared with nontargeting controls ( P < 0.01). Moreover, we evaluated low passage hPASMCs from control and patients with idiopathic pulmonary arterial hypertension (IPAH). Compared with controls, protein expression of HIF-1alpha and Twist-related protein-1 (TWIST1) was decreased ( P < 0.05), and miRNA-543 and ET-1 expression increased ( P < 0.001) in hPASMCs from patients with IPAH. Thus, in PASMCs, loss of HIF-1alpha increases miRNA-543, which decreases Twist expression, leading to an increase in PASMC ET-1 expression. This previously undescribed link between HIF-1alpha and ET-1 via miRNA-543 mediated Twist suppression represents another layer of molecular regulation that might determine pulmonary vascular tone. |
