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 (p[H.sub.i]) and we previously showed that PASMCs isolated from mice exposed to chronic hypoxia exhibited increased [Na.sup.+]/[H.sup.+] exchanger (NILE) 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 hypoxiainducible factor 1 (HIF-1). Consistent with previous results, increased NIlE isoform 1 (NHE1) mRNA and protein, enhanced NHE activity, and an alkaline shift in p[H.sub.i] were observed in PASMCs isolated from wild-type mice exposed to chronic hypoxia (3 wk at 10% [O.sub.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.sub.2]) or overexpression of HIF-1 in the absence of hypoxia also increased NHE1 rnRNA 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. hypoxia-inducible factor 1; pulmonary arterial smooth muscle cell