Transcriptomic changes triggered by hypoxia

Evidence for HIF-1α -independent, [Na+]i/[K+]i-mediated, excitation-transcription coupling

Svetlana V. Koltsova, Boris Shilov, Julia G. Birulina, Olga A. Akimova, Mounsif Haloui, Leonid V. Kapilevich, Svetlana V. Gusakova, Johanne Tremblay, Pavel Hamet, Sergei N. Orlov

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Abstract

This study examines the relative impact of canonical hypoxia-inducible factor-1alpha- (HIF-1α and Na+i/K+i-mediated signaling on transcriptomic changes evoked by hypoxia and glucose deprivation. Incubation of RASMC in ischemic conditions resulted in ∼3-fold elevation of [Na+]i and 2-fold reduction of [K+]i. Using global gene expression profiling we found that Na+, K+-ATPase inhibition by ouabain or K+-free medium in rat aortic vascular smooth muscle cells (RASMC) led to the differential expression of dozens of genes whose altered expression was previously detected in cells subjected to hypoxia and ischemia/reperfusion. For further investigations, we selected Cyp1a1, Fos, Atf3, Klf10, Ptgs2, Nr4a1, Per2 and Hes1, i.e. genes possessing the highest increments of expression under sustained Na+, K+-ATPase inhibition and whose implication in the pathogenesis of hypoxia was proved in previous studies. In ouabain-treated RASMC, low-Na+, high-K+ medium abolished amplification of the [Na+]i/[K+]i ratio as well as the increased expression of all tested genes. In cells subjected to hypoxia and glucose deprivation, dissipation of the transmembrane gradient of Na+ and K+ completely eliminated increment of Fos, Atf3, Ptgs2 and Per2 mRNAs and sharply diminished augmentation expression of Klf10, Edn1, Nr4a1 and Hes1. In contrast to low-Na+, high-K+ medium, RASMC transfection with Hif-1a siRNA attenuated increments of Vegfa, Edn1, Klf10 and Nr4a1 mRNAs triggered by hypoxia but did not impact Fos, Atf3, Ptgs2 and Per2 expression. Thus, our investigation demonstrates, for the first time, that Na+i/K+i-mediated, Hif-1α- -independent excitation-transcription coupling contributes to transcriptomic changes evoked in RASMC by hypoxia and glucose deprivation.

Original languageEnglish
Article numbere110597
JournalPLoS One
Volume9
Issue number11
DOIs
Publication statusPublished - 6 Nov 2014

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Transcription
transcriptomics
Muscle
Rats
hypoxia
Vascular Smooth Muscle
transcription (genetics)
Smooth Muscle Myocytes
blood vessels
smooth muscle
myocytes
Genes
Cells
Ouabain
rats
Glucose
Adenosine Triphosphatases
ouabain
sodium-potassium-exchanging ATPase
glucose

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Transcriptomic changes triggered by hypoxia : Evidence for HIF-1α -independent, [Na+]i/[K+]i-mediated, excitation-transcription coupling. / Koltsova, Svetlana V.; Shilov, Boris; Birulina, Julia G.; Akimova, Olga A.; Haloui, Mounsif; Kapilevich, Leonid V.; Gusakova, Svetlana V.; Tremblay, Johanne; Hamet, Pavel; Orlov, Sergei N.

In: PLoS One, Vol. 9, No. 11, e110597, 06.11.2014.

Research output: Contribution to journalArticle

Koltsova, SV, Shilov, B, Birulina, JG, Akimova, OA, Haloui, M, Kapilevich, LV, Gusakova, SV, Tremblay, J, Hamet, P & Orlov, SN 2014, 'Transcriptomic changes triggered by hypoxia: Evidence for HIF-1α -independent, [Na+]i/[K+]i-mediated, excitation-transcription coupling', PLoS One, vol. 9, no. 11, e110597. https://doi.org/10.1371/journal.pone.0110597
Koltsova, Svetlana V. ; Shilov, Boris ; Birulina, Julia G. ; Akimova, Olga A. ; Haloui, Mounsif ; Kapilevich, Leonid V. ; Gusakova, Svetlana V. ; Tremblay, Johanne ; Hamet, Pavel ; Orlov, Sergei N. / Transcriptomic changes triggered by hypoxia : Evidence for HIF-1α -independent, [Na+]i/[K+]i-mediated, excitation-transcription coupling. In: PLoS One. 2014 ; Vol. 9, No. 11.
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