Organ protection by hypoxia and hypoxia-inducible factors.
Since the first description of a protective effect of hypoxic preconditioning in the heart, the principle of reducing tissue injury in response to ischemia by prior exposure to hypoxia was confirmed in a number of cells and organs. However, despite impressive preclinical results, hypoxic preconditioning has so far failed to reach clinical application. Nevertheless, it remains of significant interest to induce genes that are normally activated during hypoxia and ischemia as part of an endogenous escape mechanism prior to or during the early phase of an ischemic insult. This approach has recently been greatly facilitated by the identification of hypoxia-inducible factors (HIFs), transcription factors that operate as a master switch in the cellular response to hypoxia. Far more than 100 target genes are regulated by HIF, including genes such as erythropoietin and hemoxygenase-1, which have been shown to be tissue-protective. The identification of small molecule inhibitors of the oxygen-sensing HIF-prolyl hydroxlases now offers the possibility to mimic the hypoxic response by pharmacological stabilization of HIF in order to achieve organ protection. Oxygen-independent activation of HIF is therefore a promising therapeutic strategy for the prevention of organ injury and failure.
Bernhardt
Wanja M
WM
Department of Nephrology and Hypertension, Friedrich-Alexander University, Erlangen, Nürnberg, Germany.
Warnecke
Christina
C
Willam
Carsten
C
Tanaka
Tetsuhiro
T
Wiesener
Michael S
MS
Eckardt
Kai-Uwe
KU
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology; D015687:Cell Hypoxia; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D007511:Ischemia / Q000517:prevention & control*; D019194:Ischemic Preconditioning / Q000379:methods*; D051379:Mice; D009206:Myocardium / Q000201:enzymology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D014157:Transcription Factors; D002248:Carbon Monoxide; D011393:Procollagen-Proline Dioxygenase