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Am J Physiol Lung Cell Mol Physiol (June 9, 2006). doi:10.1152/ajplung.00528.2005
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Submitted on December 15, 2005
Accepted on June 5, 2006

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

Larissa A. Shimoda1*, Michele Fallon1, Sarah Pisarcik1, Jian Wang1, and Gregg L. Semenza1

1 Medicine, Johns Hopkins, Baltimore, Maryland, United States

* To whom correspondence should be addressed. E-mail: shimodal{at}welch.jhu.edu.

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 pHi. 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 weeks 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 hours 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.




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