Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression.
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.
Takeshita
Kyosuke
K
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Fujimori
Toshihiko
T
Kurotaki
Yoko
Y
Honjo
Haruo
H
Tsujikawa
Hiroshi
H
Yasui
Kenji
K
Lee
Jong-Kook
JK
Kamiya
Kaichiro
K
Kitaichi
Kiyoyuki
K
Yamamoto
Koji
K
Ito
Masafumi
M
Kondo
Takahisa
T
Iino
Shigeo
S
Inden
Yasuya
Y
Hirai
Makoto
M
Murohara
Toyoaki
T
Kodama
Itsuo
I
Nabeshima
Yo-ichi
Y
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*
D002316:Cardiotonic Agents; D008565:Membrane Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins; D007545:Isoproterenol; D009638:Norepinephrine