Role of the Na/H antiport in pH-dependent cell death in pulmonary artery endothelial cells

Citation
M. Cutaia et al., Role of the Na/H antiport in pH-dependent cell death in pulmonary artery endothelial cells, AM J P-LUNG, 278(3), 2000, pp. L536-L544
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
ISSN journal
1040-0605 → ACNP
Volume
278
Issue
3
Year of publication
2000
Pages
L536 - L544
Database
ISI
SICI code
1040-0605(200003)278:3<L536:ROTNAI>2.0.ZU;2-E
Abstract
We investigated the role of intracellular pH (pH(i)) and Na/H exchange in c ell death in human pulmonary artery endothelial cells (HPAEC) following a m etabolic insult (inhibition-oxidative phosphorylation, glycolysis). Metabol ic inhibition in medium at pH 7.4 decreased viability (0-15% live cells) ov er 6 h. Cell death was attenuated by maneuvers that decreased pHi and inhib ited Na/H exchange (acidosis, Na/H antiport inhibitors). In contrast, cell death was potentiated by maneuvers that elevated pHi or increased Na/H exch ange (monensin, phorbol eater treatment) before the insult. HPAEC demonstra ted a biphasic pHi response following a metabolic insult. An initial decrea se in pHi was followed by a return to baseline over 60 min. Maneuvers that protected HPAEC and inhibited Na/H exchange (acidosis, Na+-free medium, ant iport inhibitors) altered this pattern. pHi decreased, but no recovery was observed, suggesting that the return of pHi to normal was mediated by antip ort activation. Although Na/H antiport activity was reduced (55-60% of cont rol) following a metabolic insult, the cells still demonstrated active Na/H exchange despite significant ATP depletion. Phorbol ester pretreatment, wh ich potentiated cell death, increased Na/H antiport activity above the leve l observed in monolayers subjected to a metabolic insult alone. These resul ts demonstrate that HPAEC undergo a pH-dependent loss of viability linked t o active Na/H exchange following a metabolic insult. Potentiation of cell d eath with phorbol ester treatment suggests that this cell death pathway inv olves protein kinase C-mediated phosphorylation events.