HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes.
Vascular remodeling resulting from altered pulmonary arterial smooth muscle cell (PASMC) growth is a contributing factor to the pathogenesis of hypoxic pulmonary hypertension. PASMC growth requires an alkaline shift in intracellular pH (pH(i)) and we previously showed that PASMCs isolated from mice exposed to chronic hypoxia exhibited increased Na(+)/H(+) exchanger (NHE) expression and activity, which resulted in increased pH(i). However, the mechanism by which hypoxia caused these changes was unknown. In this study we tested the hypothesis that hypoxia-induced changes in PASMC pH homeostasis are mediated by the transcriptional regulator hypoxia-inducible factor 1 (HIF-1). Consistent with previous results, increased NHE isoform 1 (NHE1) mRNA and protein, enhanced NHE activity, and an alkaline shift in pH(i) were observed in PASMCs isolated from wild-type mice exposed to chronic hypoxia (3 wk at 10% O(2)). In contrast, these changes were absent in PASMCs isolated from chronically hypoxic mice with partial deficiency for HIF-1. Exposure of PASMCs to hypoxia ex vivo (48 h at 4% O(2)) or overexpression of HIF-1 in the absence of hypoxia also increased NHE1 mRNA and protein expression. Our results indicate that full expression of HIF-1 is essential for hypoxic induction of NHE1 expression and changes in PASMC pH homeostasis and suggest a novel mechanism by which HIF-1 mediates pulmonary vascular remodeling during the pathogenesis of hypoxic pulmonary hypertension.
Shimoda
Larissa A
LA
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, JHAAC 4A.52, Baltimore, MD 21224, USA. shimodal@welch.jhu.edu
Fallon
Michele
M
Pisarcik
Sarah
S
Wang
Jian
J
Semenza
Gregg L
GL
D000136:Acid-Base Equilibrium / Q000502:physiology*; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism
D027682:Cation Transport Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; C490997:Slc9a1 protein, mouse; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers