Oxygen tension modulates the expression of pulmonary vascular BKCa channel alpha- and beta-subunits.
At birth, the lung environment changes from low to relatively high O(2) tension. Pulmonary blood flow increases and pulmonary artery pressure decreases. Recent data suggest that pulmonary vascular calcium-sensitive K(+) channel (BK(Ca)) activation mediates perinatal pulmonary vasodilation. Although BK(Ca) channel expression is developmentally regulated, the molecular mechanisms responsible for BK(Ca) expression remain unknown. We tested the hypothesis that the low-O(2) tension environment of the normal fetus modulates BK(Ca) channel expression. We analyzed BK(Ca) expression under conditions of hypoxia and normoxia both in vitro and in vivo. BK(Ca) alpha-subunit mRNA expression increased twofold in ovine pulmonary artery smooth muscle cell (PASMC) primary cultures maintained in hypoxia. In vivo, BK(Ca) expression was similarly affected by hypoxia. When adult Sprague-Dawley rats were placed in hypobaric hypoxic chambers for 3 wk, hypoxic animals showed an increase of threefold in the expression of BK(Ca) alpha- and more than twofold in the expression of BK(Ca) beta(1)-subunit mRNA. Immunochemical staining was consistent with the genetic data. To assess transcriptional activation of the beta-subunit of the BK(Ca), both BK(Ca) beta(1)- and beta(2)-subunit luciferase (K(Ca) beta:luc(+)) reporter genes were constructed. Hypoxia increased PASMC K(Ca) beta(1):luc(+) reporter expression by threefold and K(Ca) beta(2):luc(+) expression by 35%. Fetal PASMC treated with the hypoxia-inducible factor-1 mimetic deferoxamine showed a 63 and 41% increase in BK(Ca) channel alpha- and beta(1)-subunit expression, respectively. Together, these results suggest that oxygen tension modulates BK(Ca) channel subunit mRNA expression, and the regulation is, at least in part, at the transcriptional level.
Resnik
Ernesto
E
Univ. of Minnesota, Minneapolis, MN 55455, USA. resni004@umn.edu
Herron
Jean
J
Fu
Rao
R
Ivy
D Dunbar
DD
Cornfield
David N
DN
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D005333:Fetus / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009994:Osmolar Concentration; D010100:Oxygen; D010313:Partial Pressure; D010455:Peptides / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep / Q000196:embryology; D014158:Transcription, Genetic
D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D020033:Protein Isoforms; C064719:iberiotoxin; D003676:Deferoxamine; D010100:Oxygen; D002118:Calcium