Hydrogen Sulfide Inhibits Hypoxia- But Not Anoxia-Induced Hypoxia-Inducible Factor 1 Activation in a von Hippel-Lindau- and Mitochondria-Dependent Manner

Abstract

Aims: In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H 2 S) is an endogenously synthesized gaseous molecule that acts as an important signaling molecule in the living body. Transcription factor hypoxiainducible factor 1 (HIF-1) is known to respond to intracellular reduced oxygen (O 2 ) availability, which is regulated by an elaborate balance between O 2 supply and demand. However, the effect of H 2 S on HIF-1 activity under hypoxic conditions is largely unknown in mammalian cells. In this study, we tried to elucidate the effect of H 2 S on hypoxia-induced HIF-1 activation adopting cultured cells and mice. Results: The H 2 S donors sodium hydrosulfide and sodium sulfide in pharmacological concentrations reversibly reduced cellular O 2 consumption and inhibited hypoxia-but not anoxia-induced HIF-1a protein accumulation and expression of genes downstream of HIF-1 in established cell lines. H 2 S did not affect HIF-1 activation induced by the HIF-a hydroxylases inhibitors desferrioxamine or CoCl 2 . Experimental evidence adopting von Hippel-Lindau (VHL)-or mitochondria-deficient cells indicated that H 2 S did not affect neosynthesis of HIF-1a protein but destabilized HIF-1a in a VHL-and mitochondria-dependent manner. We also demonstrate that exogenously administered H 2 S inhibited HIF-1-dependent gene expression in mice. Innovation: For the first time, we show that H 2 S modulates intracellular O 2 homeostasis and regulates activation of HIF-1 and the subsequent gene expression induced by hypoxia by using an in vitro system with established cell lines and an in vivo system in mice. Conclusions: We demonstrate that H 2 S inhibits hypoxia-induced HIF-1 activation in a VHL-and mitochondriadependent manner. Antioxid. Redox Signal. 16,[203][204][205][206][207][208][209][210][211][212][213][214][215][216]

Aglycemia keeps mitochondrial oxidative phosphorylation under hypoxic conditions in HepG2 cells

“…Likewise, hydrogen sulfide may participate in the non-canonical HIF response (Kai et al 2012). Apoptosis is also closely linked to the cell's bioenergetic mechanism (Jose and Rossignol 2013;Zhang and Yang 2013) and this explains the higher sensitivity to apoptosis at the maintained level of mitochondrial activity in hypoxia-adapted OXPHOS cells.…”

H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2

“…Others studies have indicated that the inhibition of cell proliferation by H 2 S is involved in the stabilization of p53 coupled with the induction of downstream molecules, including p21 and Bax (40). Notably, a recent study demonstrated that H 2 S inhibits both HIF-1α translation by enhancing the phosphorylation of eukaryotic translation initiation factor 2α (41); another study demonstrated that H 2 S inhibits the activation of HIF-1α in a von Hippel-Lindau protein-and mitochondrial-dependent manner (42). In this study, treatment with H 2 S markedly upregulated COX-2 expression and enhanced PGI 2 secretion from CoCl 2 -stimulated HPASMCs, which may be associated with the inhibition of HIF-1α.…”

Systematic review with meta-analysis: HIF-1α attenuates liver ischemia–reperfusion injury

“…The 31 included animal studies score ranging from 2 to 6 (see Table 2), and contained 4 studies ranked A [18,19,45,50], 23 ranked B [15][16][17]23,24,27,28,[30][31][32][33][34][35][36][37][38]43,44,[46][47][48][49]51], and 4 ranked C [26,29,39,42]. In subject classification, the study of intervention gets the highest marks, owing to better control of temperature and blinded assessment of outcome.…”