title: Impaired nitric oxide production and increased blood pressure in systemic heterozygous ATP2B1 null mice.
abstract: BACKGROUND
  In the 'Millennium Genome Project', we identified ATP2B1 as a gene responsible for hypertension through single-nucleotide polymorphism analysis. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which contributes to the maintenance of intracellular calcium homeostasis by removing calcium ions.
  
  
  METHODS
  Since ATP2B1 knockout mice are reported to be embryo-lethal, we generated systemic heterozygous ATP2B1 null (ATP2B1(+/-)) mice, and evaluated the implication of ATP2B1 in blood pressure.
  
  
  RESULTS
  ATP2B1(+/-) mice revealed significantly higher SBP as measured by a radiotelemetric method. Phenylephrine-induced vasoconstriction was significantly increased in vascular rings from ATP2B1(+/-) mice, and the difference in this contraction disappeared in the presence of a nitric oxide synthase (NOS) inhibitor. Vasorelaxation to acetylcholine was significantly attenuated in vascular rings from ATP2B1(+/-) mice. In addition, cultured endothelial cells of ATP2B1(+/-) mice showed that the phosphorylation (Ser-1177) level of endothelial NOS protein was significantly lower, and nitric oxide production in endothelial cells and aorta was lower compared with those in control mice. In contrast, neural NOS expression in vascular smooth muscle cells from ATP2B1(+/-) mice and control mice were not significantly different.
  
  
  CONCLUSIONS
  These results suggest that decreased ATP2B1 gene expression is associated with impaired endothelial NOS activity and nitric oxide production, and the ATP2B1 gene plays a crucial role in the regulation of blood pressure.
authors.affiliation: aDepartment of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine bDepartment of Nephrology and Hypertension, Yokohama City University Medical Center cMolecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama dCenter for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto eDepartment of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon fDepartment of Health Science, Shiga University of Medical Science, Otsu gCardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fujiwara
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Hirawa
authors.forename: Megumi
authors.initials: M
authors.lastname: Fujita
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okuyama
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yatsu
authors.forename: Mari
authors.initials: M
authors.lastname: Katsumata
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Naoaki
authors.initials: N
authors.lastname: Ichihara
authors.forename: Sanae
authors.initials: S
authors.lastname: Saka
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Toya
authors.forename: Gen
authors.initials: G
authors.lastname: Yasuda
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Goshima
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Tabara
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Miki
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Ueshima
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000235:genetics; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D002118:Calcium; D000252:Calcium-Transporting ATPases; D009569:Nitric Oxide; D053499:Plasma Membrane Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; C499849:NCX1 protein, mouse; C000589038:ATP2B4 protein, mouse; C506954:Atp2b1 protein, mouse