title: Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia.
abstract: BACKGROUND
  Chronic hypoxia is one of the major causes of pulmonary vascular remodeling associated with stimulating reactive oxygen species (ROS) production. Recent studies have indicated that hypoxia upregulates expression of adrenomedullin (AM), which is not only a potent vasodilator but also an antioxidant. Thus, using heterozygous AM-knockout (AM+/-) mice, we examined whether AM could attenuate pulmonary vascular damage induced by hypoxia.
  
  
  RESULTS
  Ten-week-old male wild-type (AM+/+) or AM+/- mice were housed under 10% oxygen conditions for 3 to 21 days. In AM+/+ mice, hypoxia enhanced AM mRNA expression, which was reduced by the administration of a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Hypoxia induced pulmonary vascular remodeling, which was associated with the increased production of oxidative stress measured by electron spin resonance and immunostaining of 3-nitrotyrosine. The media wall thickness of the pulmonary arteries was significantly greater in AM+/- mice housed under hypoxia than in AM+/+ mice under hypoxia. Concomitantly, pulmonary ROS production induced by hypoxia was more enhanced in AM+/- mice than in AM+/+ mice. The administration of both exogenous AM and hydroxy-TEMPO normalized pulmonary vascular media wall thickness in not only AM+/+ but also AM+/- mice under hypoxic conditions associated with the normalization of ROS overproduction in the lung.
  
  
  CONCLUSIONS
  The present results suggest that an endogenous AM is a potential protective peptide against hypoxia-induced vascular remodeling, possibly through the suppression of ROS generation, which might provide an effective therapeutic strategy.
authors.affiliation: Department of Nephrology and Endocrinology, Faculty of Medicine, the University of Tokyo, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Matsui
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.forename: Kanami
authors.initials: K
authors.lastname: Itakura
authors.forename: Xing
authors.initials: X
authors.lastname: Guanqun
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Ando
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002908:Chronic Disease; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species; D013113:Spin Labels; D017540:Tunica Media / Q000648:ultrastructure
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D010455:Peptides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013113:Spin Labels; D053607:Adrenomedullin; C001803:tempol