title: Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity.
abstract: Atherosclerotic lesions represent a hypoxic milieu. However, the significance of this milieu in atherothrombosis has not been established. We aimed to assess the hypothesis that vascular wall hypoxia promotes arterial thrombus formation. We examined the relation between vascular wall hypoxia and arterial thrombus formation using a rabbit model in which arterial thrombosis was induced by 0.5 %-cholesterol diet and repeated balloon injury of femoral arteries. Vascular wall hypoxia was immunohistochemically detected by pimonidazole hydrochloride, a hypoxia marker. Rabbit neointima and THP-1 macrophages were cultured to analyse prothrombotic factor expression under hypoxic conditions (1 % O2). Prothrombotic factor expression and nuclear localisation of hypoxia-inducible factor (HIF)-1α and nuclear factor-kappa B (NF-κB) p65 were immunohistochemically assessed using human coronary atherectomy plaques. Hypoxic areas were localised in the macrophage-rich deep portion of rabbit neointima and positively correlated with the number of nuclei immunopositive for HIF-1α and NF-κB p65, and tissue factor (TF) expression. Immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly correlated with hypoxic areas in arteries. TF and plasminogen activator inhibitor-1 (PAI-1) expression was increased in neointimal tissues and/or macrophages cultured under hypoxia, and both were suppressed by inhibitors of either HIF-1 or NF-κB. In human coronary plaques, the number of HIF-1α-immunopositive nuclei was positively correlated with that of NF-κB-immunopositive nuclei and TF-immunopositive and PAI-1-immunopositive area, and it was significantly higher in thrombotic plaques. Vascular wall hypoxia augments the thrombogenic potential of atherosclerotic plaque and thrombus formation on plaques via prothrombotic factor upregulation.
authors.forename: Yunosuke
authors.initials: Y
authors.lastname: Matsuura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamashita
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwakiri
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sugita
authors.forename: Nozomi
authors.initials: N
authors.lastname: Okuyama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Yujiro Asada, MD, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan, Tel.: + 81 985 85 2810, Fax: + 81 985 85 7614, E-mail: yasada@med.miyazaki-u.ac.jp.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Asada
mesh_terms: D000368:Aged; D000800:Angioplasty, Balloon; D000818:Animals; D050197:Atherosclerosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D002460:Cell Line; D002791:Cholesterol, Dietary; D003324:Coronary Artery Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058426:Neointima; D058226:Plaque, Atherosclerotic; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011817:Rabbits; D012307:Risk Factors; D015398:Signal Transduction; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D046509:Tissue Culture Techniques; D051996:Transcription Factor RelA / Q000378:metabolism; D057772:Vascular System Injuries / Q000150:complications* / Q000378:metabolism / Q000473:pathology
chemical_list: D002791:Cholesterol, Dietary; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017395:Plasminogen Activator Inhibitor 1; C498143:RELA protein, human; C051321:SERPINE1 protein, human; D051996:Transcription Factor RelA; D013925:Thromboplastin
keywords: Atherothrombosis; hypoxia; hypoxia-inducible factor-1; nuclear factor-κB; tissue factor