January 2018• Volume 126• Number 1 www. anesthesia-analgesia. org 309 targeted therapeutically in patients as a potential treatment approach for the prevention or treatment of perioperative organ injury. This is particularly important due to the fact that many surgical procedures are performed electively and thereby provides the opportunity to introduce prophylactic treatment approaches to prevent perioperative organ injuries. Furthermore, future strategies may allow identification of patients at risk for a specific type of organ injury and facilitate the implementation of preventative measures. 12 The oxygen-sensing pathway and detailed regulation of HIFs are illustrated in Figure 2. Briefly, HIFs are αβheterodimeric transcription factors that are essential to hypoxia adaptation, orchestrating transcriptional programs that regulate metabolism and maintain tissue homeostasis during hypoxic conditions. 13, 14 Under normal oxygen levels, HIF-1α and HIF-2α proteins are rapidly degraded in a process that involves hydroxylation by oxygen-sensing prolyl hydroxylases (PHDs) and binding of the von Hippel-Lindau (VHL) gene product. 15, 16 This process promotes polyubiquitination and subsequent proteasomal degradation. Hypoxic conditions result in the functional inhibition of PHDs because PHDs require oxygen as cofactor, which stops the hydroxylation and in turn stabilizes HIFs. 17 Upon stabilization, HIF-1α forms a complex with the β-subunit and translocates into the nucleus to mediate transcriptional regulation by binding to hypoxia-responsive elements of target genes. 18, 19 Interestingly, it is estimated that over 5% of all human genes are direct target genes of HIFs, which include genes that control cell metabolism, modulate inflammation, regulate apoptosis, and promote angiogenesis. 20 Thus, targeting hypoxia signaling via modulation of HIFs may potentially have a profound impact on perioperative organ injury. Studying the HIF pathway for organ protection appears to be highly timely, as the 2016 Albert