Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells.
Chronic hypoxia (CH) causes pulmonary vasoconstriction because of increased pulmonary arterial smooth muscle cell (PASMC) contraction and proliferation. We previously demonstrated that intracellular Ca(2+) concentration ([Ca(2+)](i)) was elevated in PASMCs from chronically hypoxic rats because of Ca(2+) influx through pathways other than L-type Ca(2+) 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 Ca(2+) channels (SOCCs) and the regulation of these channels by HIF-1. Capacitative Ca(2+) entry (CCE) was enhanced in PASMCs from intrapulmonary arteries of rats exposed to CH (10% O(2); 21 days), and exposure to Ca(2+)-free extracellular solution or SOCC antagonists (SKF96365 or NiCl(2)) decreased resting [Ca(2+)](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% O(2); 60 hours), and in PASMCs in which HIF-1 was overexpressed under nonhypoxic conditions. Hypoxia-induced increases in basal [Ca(2+)](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 Ca(2+) influx and increasing basal [Ca(2+)](i) in PASMCs and that this response is mediated by HIF-1.
Wang
Jian
J
Division of Pulmonary and Critical Care Medicine, Institute for Cell Engineering, Baltimore, Md., USA.
Weigand
Letitia
L
Lu
Wenju
W
Sylvester
J T
JT
Semenza
Gregg L
GL
Shimoda
Larissa A
LA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000172:deficiency / Q000378:metabolism*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009994:Osmolar Concentration; D011651:Pulmonary Artery / Q000378:metabolism*; D051381:Rats; D050052:TRPC Cation Channels / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D051793:Hypoxia-Inducible Factor 1; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; C096351:transient receptor potential cation channel, subfamily C, member 1; D002118:Calcium