HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes

Larissa A. Shimoda, Michele Fallon, Sarah Pisarcik, Jian Wang, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

Abstract

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 (pHi) 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 pHi were observed in PASMCs isolated from wild-type mice exposed to chronic hypoxia (3 wk at 10% O2). 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% O2) 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.

Original languageEnglish (US)
Pages (from-to)L941-L949
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume291
Issue number5
DOIs
StatePublished - 2006

Keywords

  • Hypoxia-inducible factor 1
  • Pulmonary arterial smooth muscle cell

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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