Published online before print May 18, 2006, doi: 10.1161/01.RES.0000227551.68124.98
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Submitted on August 22, 2005
Revised on April 27, 2006
Accepted on May 8, 2006
Hypoxia Inducible Factor 1 Mediates Hypoxia-Induced TRPC Expression and Elevated Intracellular Ca2+ in Pulmonary Arterial Smooth Muscle Cells
Jian Wang ;
From the Division of Pulmonary and Critical Care Medicine; Vascular Biology Program, Institute for Cell Engineering; Departments of Medicine, Pediatrics, Oncology, and Radiation Oncology; and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: shimodal{at}welch.jhu.edu.
Chronic hypoxia (CH) causes pulmonary vasoconstriction because of increased pulmonary arterial smooth muscle cell (PASMC) contraction and proliferation. We previously demonstrated that intracellular Ca2+ concentration ([Ca2+]i) was elevated in PASMCs from chronically hypoxic rats because of Ca2+ influx through pathways other than L-type Ca2+ channels and that development of hypoxic pulmonary hypertension required full expression of the transcription factor hypoxia inducible factor 1 (HIF-1). In this study, we examined the effect of CH on the activity and expression of store-operated Ca2+ channels (SOCCs) and the regulation of these channels by HIF-1. Capacitative Ca2+ entry (CCE) was enhanced in PASMCs from intrapulmonary arteries of rats exposed to CH (10% O2; 21 days), and exposure to Ca2+-free extracellular solution or SOCC antagonists (SKF96365 or NiCl2) decreased resting [Ca2+]i in these cells. Expression of TRPC1 and TRPC6, but not TRPC4, mRNA and protein was increased in PASMCs from rats and wild-type mice exposed to CH, in PASMCs from normoxic animals cultured under hypoxic conditions (4% O2; 60 hours), and in PASMCs in which HIF-1 was overexpressed under nonhypoxic conditions. Hypoxia-induced increases in basal [Ca2+]i and TRPC expression were absent in mice partially deficient for HIF-1. These results suggest that increased TRPC expression, leading to enhanced CCE through SOCCs, may contribute to hypoxic pulmonary hypertension by facilitating Ca2+ influx and increasing basal [Ca2+]i in PASMCs and that this response is mediated by HIF-1.
Key words: Ca2+ channels • hypoxia • hypoxia-inducible factor 1 • hypoxic pulmonary vasoconstriction • vascular smooth muscle
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