title: Adrenomedullin, an endogenous peptide, counteracts cardiovascular damage.
abstract: BACKGROUND
  Adrenomedullin (AM), a potent vasodilator peptide, is produced by posttranslational splicing of pro-adrenomedullin together with proadrenomedullin N-terminal 20 peptide (PAMP), another hypotensive peptide. Although both AM and PAMP have the potential not only to decrease blood pressure but also to protect organs from damage, there is no direct evidence for their individual physiological roles in vivo.
  
  
  RESULTS
  Using knockout mice with the disruption of AM peptide alone, we investigated the organ-protective effect of AM. Although the AM(-/-) mutation in mice was embryonic lethal without any apparent phenotypic changes, AM(+/-) mice were viable and fertile; plasma and organ AM concentrations were almost half of those in AM(+/+) mice. With the administration of angiotensin II (Ang II) on a high-salt diet for 12 days, marked perivascular fibrosis and intimal hyperplasia were found in coronary arteries of Ang II/salt-treated AM(+/-) mice, without the AM upregulation that was observed in Ang II/salt-treated AM(+/+) mice. In AM(+/-) mice, Ang II/salt loading increased both urinary excretion of 8-hydroxydeoxyguanosine and isoprostane, markers of oxidative stress. Consistently, immunostaining of both p67phox and gp91phox, subunits of NAD(P)H oxidase and 3-nitrotyrosine, the metabolites of reactive oxygen species (ROS), and the generation of ROS measured by electron spin resonance spectroscopy apparently increased in the Ang II/salt-treated heart. These data suggested that the overproduction of oxidative stress might be involved in the cardiovascular changes induced by Ang II/salt loading.
  
  
  CONCLUSIONS
  The evidence presented supports the hypothesis that endogenous AM possesses a protective action against cardiovascular damage, possibly through the inhibition of oxidative stress production.
authors.affiliation: Department of Nephrology and Endocrinology, Faculty of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.forename: Yugo
authors.initials: Y
authors.lastname: Shibagaki
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Ando
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D053607:Adrenomedullin; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002318:Cardiovascular Diseases / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005838:Genotype; D008168:Lung / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism; D010455:Peptides / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000652:urine; D012982:Sodium, Dietary / Q000008:administration & dosage; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D010455:Peptides; D010750:Phosphoproteins; D011506:Proteins; D017382:Reactive Oxygen Species; D012982:Sodium, Dietary; C079789:neutrophil cytosol factor 67K; D000804:Angiotensin II; D053607:Adrenomedullin; C002744:3-nitrotyrosine; D014443:Tyrosine; D009247:NADH, NADPH Oxidoreductases; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases