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This Article Full Text Full Text (PDF) All Versions of this Article: 291/5/L941    most recent 00528.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Shimoda, L. A. Articles by Semenza, G. L. Search for Related Content PubMed PubMed Citation Articles by Shimoda, L. A. Articles by Semenza, G. L.

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

¹Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine; ²Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 15 December 2005 ; accepted in final form 5 June 2006

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% 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.

hypoxia-inducible factor 1; pulmonary arterial smooth muscle cell

This article has been cited by other articles:

				L. Yu, D. A. Quinn, H. G. Garg, and C. A. Hales Deficiency of the NHE1 Gene Prevents Hypoxia-induced Pulmonary Hypertension and Vascular Remodeling Am. J. Respir. Crit. Care Med., June 1, 2008; 177(11): 1276 - 1284. [Abstract] [Full Text] [PDF]