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]

Cigarette smoke (CS) is a major contributor to the development of a large number of fatal and debilitating disorders. However, the precise molecular mechanisms underlying the effects of CS in lung disease are largely unknown. To elucidate these pathophysiological processes, we examined the in vitro and in vivo effects of CS extract (CSE) and CS on the transcription factor, hypoxia-inducible factor 1 (HIF-1). CSE induced concentration- and time-dependent accumulation of HIF-1α protein in human lung epithelial-like cells under non-hypoxic conditions. Genes upregulated by HIF-1, including vascular endothelial growth factor and regulated in development and DNA damage response 1, both of which are involved in smoking-induced emphysematous changes, were increased by CSE treatment under non-hypoxic conditions in vitro and in vivo. Further investigation revealed that reactive oxygen species were generated in cells exposed to CSE and were required for CSE-mediated induction of HIF-1α protein, as was activation of phosphoinositide 3-kinase and mitogen-activated protein kinase pathways. In conclusion, we demonstrated that CSE and CS induced HIF-1 activation in vitro and in vivo, respectively. The evidence warrants further investigation to indicate that HIF-1 plays an important role in CS-induced gene expression, which is deeply involved in pulmonary cellular stress and small airway remodelling.

Our experimental results indicate that propofol inhibits HIF-1 activation and downstream gene expression induced by LPS and suppressed HIF-1-dependent glucose metabolic reprogramming. HIF-1 suppression by propofol in macrophages may explain molecular mechanisms behind the inhibitory effect of propofol on cellular inflammatory responses.

BackgroundErythropoietin (EPO), originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS). EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF)-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes.Methodology/Principal FindingsBALB/c mice were exposed to 10% oxygen with isoflurane at various concentrations (0.10–1.0%). Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2α protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2α protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2α protein and EPO mRNA.Conclusions/SignificanceTaken together, our results indicate that general anesthetics suppress activation of HIF-2 and inhibit hypoxia-induced EPO upregulation in the mouse brain through a direct effect on astrocytes.

Postoperative OI was common in patients after VATS and significantly associated with delayed ambulation. Advanced age, female gender, and postoperative opioid use were identified as independent predisposing factors for OI.