title: Regulation of the HIF-system in human macrophages--differential regulation of HIF-α subunits under sustained hypoxia.
abstract: Macrophages are often associated to pathophysiological processes and were found at hypoxic areas. However, cell adaption greatly depends on hypoxia-inducible factors (HIF). Activation of these transcription factors is induced by heterodimerization of an α-(HIF-1α, -2α, -3α) and HIF-1β subunit. The main regulatory pathway is represented by α-subunit stability. Beside, little is known about the exact mechanisms of fine-tuning in Hif-regulation. The present study characterizes the hypoxia-induced regulation of HIF-1α and -2α in human macrophages. The hypoxic increase of both subunits is initially mediated by protein stabilization. Sustained hypoxia caused a distinct regulation of HIF-1α and -2α. The striking increase of HIF-2α protein expression was contrasted by a dramatic decrease of HIF-1α. The long-term downregulation of HIF-1α is due to downregulation of its mRNA. This decrease was accompanied by increased expression of ahif, a natural cis-antisense transcript of HIF-1α. The ahif-transcript was strongly inducible by hypoxia and rapidly degraded under reoxygenation. Using an adenoviral overexpression and siRNA silencing approach revealed that the targeted regulation of ahif is mediated by the HIF-system itself. Furthermore it could be shown that ahif indeed is able to modulate the hypoxic expression of HIF-1α and influences the expression of the HIF-target gene Enolase-2. Taken together, this study characterizes a new regulation process of the HIF-transcription factor-system in human macrophages under hypoxia. For the first time evidence is provided that ahif is regulated by the HIF-system and influences HIF-1α expression in primary human macrophages.
authors.affiliation: Department of Internal Medicine and Cardiology, Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany. Electronic address: david.poitz@tu-dresden.de.
authors.forename: David M
authors.initials: DM
authors.lastname: Poitz
authors.forename: Antje
authors.initials: A
authors.lastname: Augstein
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hesse
authors.forename: Marian
authors.initials: M
authors.lastname: Christoph
authors.forename: Karim
authors.initials: K
authors.lastname: Ibrahim
authors.forename: Rüdiger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Strasser
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmeißer
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D014158:Transcription, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human
keywords: Ahif; Antisense; HIF; Hypoxia-inducible factors; Macrophages