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Regulation of Aquaporin 1 Expression by Hypoxia‐Inducible Factors (HIFs) in Pulmonary Arterial Smooth Muscle Cells (PASMCs)
Author(s) -
Yun Xin,
Jiang Haiyang,
Shimoda Larissa
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.550.2
Subject(s) - aquaporin 1 , hypoxia (environmental) , hypoxic pulmonary vasoconstriction , hypoxia inducible factors , transcription factor , chemistry , microbiology and biotechnology , medicine , endocrinology , biology , vasoconstriction , biochemistry , gene , water channel , mechanical engineering , organic chemistry , oxygen , engineering , inlet
Prolonged exposure to hypoxia is a common cause of pulmonary hypertension (PH), the pathophysiology of which is characterized by sustained active vasoconstriction and pulmonary vascular remodeling. Studies have shown that HIFs, hypoxia responsive transcription factors, contribute to the development of PH. Three HIF family members have been identified, HIF‐1, HIF‐2, and HIF‐3, of which HIF‐1 and HIF‐2 are the best studied. We have shown that the water channel, aquaporin 1 (AQP1), is expressed in PASMCs and that AQP1 levels are elevated during hypoxia and mediate hypoxia‐induced cell proliferation and migration. The AQP1 promoter contains a HIF binding site, and links between HIF‐1 and AQP1 have been reported in cancer cells, suggesting AQP1 might be a direct HIF target. Thus, we wanted to determine whether either HIF‐1 or HIF‐2 regulates AQP1 in PASMCs. DMOG, which inhibits HIF protein degradation, was used to mimic hypoxia. PASMCs acutely incubated with DMOG exhibited a time‐dependent increase in the levels of AQP1 protein, but not mRNA, whereas both the protein and mRNA levels of a canonical HIF target, GLUT1, were increased. Since we previously reported a link between HIFs and intracellular calcium concentration ([Ca 2+ ] i ), as well as a link between [Ca 2+ ] i and AQP1 protein levels, we next determined whether the effects of DMOG on AQP1 were mediated by an increase in [Ca 2+ ] i . Incubation with DMOG caused an increase in [Ca 2+ ] i in PASMCs that was partially prevented by selectively inhibiting either HIF‐1 or HIF‐2. Both inhibitors also partially blocked the DMOG‐induced upregulation of AQP1 protein. When applied together, inhibitors of both HIFs completely blocked the effects of DMOG on [Ca 2+ ] i and AQP1 expression. Thus, our results demonstrate that, in PASMCs, AQP1 protein can be upregulated by both HIF‐1 and HIF‐2, not as a direct target for HIF transcriptional regulation, but rather by a mechanism involving protein accumulation secondary to HIF‐dependent increases in [Ca 2+ ] i . Support or Funding Information HL126514 18POST34030262 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .