Pathways regulating HIF-1α synthesis/degradation under normoxia and schematic illustration of H2S effects on HIF-1α accumulation under hypoxia. (a) HIF-1α protein translation under normoxia is mainly dependent on activation of the PtdIns3K-Akt mammalian target of rapamycin (mTOR). HIF-1α is hydroxylated by the prolyl hydroxylase (PHD) under normoxia. Hydroxylated HIF-1α is then bound by the von Hippel Lindau protein (pVHL). This complex in turn recruits a ubiquitin ligase that targets HIF-1α for its proteasomal degradation. (b) Under hypoxia, H2S induces phosphorylation of translation initiation factor 2α (eIF2α). Phosphorylated eIF2α inhibits HIF-1α translation. In addition, H2S decreases cellular oxygen (O2) consumption under hypoxia and reverses hypoxia-induced inhibition of PHD activity. Thus, H2S enhances degradation of HIF-1α. Abbreviations: Ub, ubiquitin.