title: Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression.
abstract: BACKGROUND
  Homozygous mutant mice with a defect of klotho gene expression (kl/kl) show multiple age-related disorders and premature death from unknown causes.
  
  
  RESULTS
  The kl/kl mice subjected to 20-hour restraint stress showed a high rate (20/30) of sudden death, which was associated with sinoatrial node dysfunction (conduction block or arrest). Heart rate and plasma norepinephrine of kl/kl mice, unlike those of wild-type (WT) mice, failed to increase during the stress. Intrinsic heart rate after pharmacological blockade of autonomic nerves in kl/kl mice was significantly lower than that in WT mice (380+/-33 versus 470+/-44 bpm; n=7). The sinus node recovery time after an overdrive pacing (600 bpm, 30 seconds) in kl/kl mice was significantly longer than in WT mice (392+/-37 versus 233+/-24 ms; n=6). In isolated sinoatrial node preparations, the positive chronotropic effect of isoproterenol was significantly less, whereas the negative chronotropic effect of acetylcholine was significantly greater in kl/kl than in WT mice. There was no degenerative structural change in the sinoatrial node of kl/kl mice. The precise localization of klotho was analyzed in newly prepared klotho-null mice with a reporter gene system (kl(-geo)). Homozygous kl(-geo) mice showed characteristic age-associated phenotypes that were almost identical to those of kl/kl mice. In the kl(-geo) mice, klotho expression was recognized exclusively in the sinoatrial node region in the heart in addition to parathyroid, kidney, and choroid plexus.
  
  
  CONCLUSIONS
  In the heart, klotho is expressed solely at the sinoatrial node. klotho gene expression is essential for the sinoatrial node to function as a dependable pacemaker under conditions of stress.
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujimori
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kurotaki
authors.forename: Haruo
authors.initials: H
authors.lastname: Honjo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsujikawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Yasui
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kamiya
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Kitaichi
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kondo
authors.forename: Shigeo
authors.initials: S
authors.lastname: Iino
authors.forename: Yasuya
authors.initials: Y
authors.lastname: Inden
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirai
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
authors.forename: Yo-ichi
authors.initials: Y
authors.lastname: Nabeshima
mesh_terms: D019588:Aging, Premature / Q000235:genetics*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D003645:Death, Sudden / Q000209:etiology*; D018390:Gene Targeting; D017930:Genes, Reporter; D005966:Glucuronidase; D006323:Heart Arrest / Q000209:etiology / Q000503:physiopathology*; D006339:Heart Rate; D007545:Isoproterenol / Q000494:pharmacology; D000090265:Klotho Proteins; D007763:Lac Operon; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D009928:Organ Specificity; D012149:Restraint, Physical; D012848:Sinoatrial Block / Q000209:etiology / Q000503:physiopathology*; D012849:Sinoatrial Node / Q000503:physiopathology*; D013312:Stress, Physiological / Q000097:blood / Q000235:genetics / Q000503:physiopathology*
chemical_list: D002316:Cardiotonic Agents; D008565:Membrane Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins; D007545:Isoproterenol; D009638:Norepinephrine