title: Heme oxygenase-1 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans.
abstract: OBJECTIVE
  Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 determines the extent of vascular dysfunction in mice and humans.
  
  
  RESULTS
  Decreased HO-1 activity and expression was paralleled by increased aortic expression and activity of the nicotinamide dinucleotide phosphate oxidase Nox2 in HO-1 deficient Hmox1⁻/⁻ and Hmox1(⁺/⁻) compared with Hmox1⁺/⁺ mice. When subjected to angiotensin II-infusion, streptozotocin-induced diabetes mellitus and aging, HO-1 deficient mice showed increased vascular dysfunction inversely correlated with HO activity. In a primary prevention population-based cohort, we assessed length polymorphisms of the HMOX1 promoter region and established a bipolar frequency pattern of allele length (long vs. short repeats) in 4937 individuals. Monocytic HMOX1 mRNA expression was positively correlated with flow-mediated dilation and inversely with CD14 mRNA expression indicating pro-inflammatory monocytes in 733 hypertensive individuals of this cohort. Hmox1⁻/⁻ mice showed drastically increased expression of the chemokine receptor CCR2 in monocytes and the aorta. Angiotensin II-infused Hmox1⁻/⁻ mice had amplified endothelial inflammation in vivo, significantly increased aortic infiltration of pro-inflammatory CD11b⁺ Ly6C(hi) monocytes and Ly6G⁺ neutrophils and were marked by Ly6C(hi) monocytosis in the circulation and an increased blood pressure response. Finally, individuals with unfavourable HMOX1 gene promoter length had increased prevalence of arterial hypertension and reduced cumulative survival after a median follow-up of 7.23 years.
  
  
  CONCLUSIONS
  Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality.
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany wenzelp@uni-mainz.de.
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.affiliation: Department of Laboratory Medicine, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Rossmann
authors.affiliation: University Heart Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kossmann
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Arnold
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Canan
authors.initials: C
authors.lastname: Simsek
authors.affiliation: Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Lagrange
authors.affiliation: Laboratory of Chronobiology, Charité University Medical Center Berlin, Hessische Str. 3-4, 10115 Berlin, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Klemz
authors.affiliation: Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönfelder
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Brandt
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Karbach
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.affiliation: Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Finger
authors.affiliation: Department of Laboratory Medicine, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Neukirch
authors.affiliation: Department of Laboratory Medicine, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Häuser
authors.affiliation: Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Manfred E
authors.initials: ME
authors.lastname: Beutel
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.affiliation: University Heart Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Germany.
authors.forename: Renate B
authors.initials: RB
authors.lastname: Schnabel
authors.affiliation: Department of Laboratory Medicine, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Lackner
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Wild
authors.affiliation: University Heart Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.affiliation: University Heart Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: Department of Medicine 2, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000818:Animals; D003430:Cross-Sectional Studies; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006973:Hypertension / Q000401:mortality / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000502:physiology; D009504:Neutrophils / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D051547:Heme Oxygenase-1
keywords: Angiotensin II; Endothelial function; Heme oxygenase-1; Hypertension/high blood pressure; Population studies