title: Deletion of hypoxia-inducible factor-1α in myeloid lineage exaggerates angiotensin II-induced formation of abdominal aortic aneurysm.
abstract: Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates various genes responding to hypoxic conditions. We previously reported that myeloid-specific activation of HIF-1α had protective effects on hypertensive cardiovascular remodelling in mice. However the role of myeloid lineage HIF-1α in the development of abdominal aortic aneurysm (AAA) has not been determined. Myeloid-specific HIF-1α knockout (HIF-1KO) mice were created using a Cre-lox recombination system in the background of apolipoprotein E-deficient (ApoE-/-) mice. HIF-1KO and control mice were fed high-fat diet (HFD) and infused with angiotensin II (Ang II, 1800 ng/kg/min) by an osmotic mini pump for 4 weeks to induce AAA formation. Deletion of HIF-1α increased aortic external diameter (2.47±0.21 mm versus 1.80±0.28 mm in control,P=0.035). AAA formation rate (94.4% in HIF-1KO versus 81.8% in control) was not statistically significant. Elastic lamina degradation grade determined by Elastica van Gieson (EVG) staining was deteriorated in HIF-1KO mice (3.91±0.08 versus 3.25±0.31 in control,P=0.013). The number of infiltrated macrophages into the abdominal aorta was increased in HIF-1KO mice. Expression of tissue inhibitors of metalloproteinases (TIMPs) was suppressed in the aorta and peritoneal macrophages (PMs) from HIF-1KO mice compared with control mice. HIF-1α in myeloid lineage cells may have a protective role against AAA formation induced by Ang II and HFD inApoE-/-mice.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahara
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan ttokunou@cardiol.med.kyushu-u.ac.jp.|Center for Disruptive Cardiovascular Medicine, Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University, Fukuoka, Japan.
authors.forename: Tomotake
authors.initials: T
authors.lastname: Tokunou
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.|Center for Disruptive Cardiovascular Medicine, Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D016019:Survival Analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D000804:Angiotensin II
keywords: abdominal aortic aneurysm; hypoxia-inducible factor; macrophage; matrix metalloproteinase; tissue inhibitor of metalloproteinase