Published Online
on March 22, 2004

A more recent version of this article appeared on April 13, 2004

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Submitted on August 12, 2003
Revised on December 3, 2003
Accepted on December 22, 2003

Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of klotho Gene Expression

Kyosuke Takeshita MD, PhD, Toshihiko Fujimori PhD, Yoko Kurotaki; , Haruo Honjo MD, PhD, Hiroshi Tsujikawa MD, Kenji Yasui MD, PhD, Jong-Kook Lee MD, PhD, Kaichiro Kamiya MD, PhD, Kiyoyuki Kitaichi PhD, Koji Yamamoto MD, PhD, Masafumi Ito MD, PhD, Takahisa Kondo MD, PhD, Shigeo Iino MD, PhD, Yasuya Inden MD, PhD, Makoto Hirai MD, PhD, Toyoaki Murohara MD, PhD, Itsuo Kodama MD, PhD, and Yo-ichi Nabeshima MD, PhD^*

From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya (K.T., T.K., S.I., Y.I., M.H., T.M.); Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto (T.F., Y.K., H.T., Y.N.); Research Institute of Environmental Medicine and Department of Health Medicine, Nagoya University, Nagoya (H.H., K.Y., J.L., K. Kamiya, I.K.); Department of Molecular Medicine and Clinical Science, Nagoya University Graduate School of Medicine, Nagoya (K. Kitaichi); Division of Pathology, Clinical Laboratory, Nagoya University Hospital, Nagoya (M.I.); and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (Y.K., Y.N.), Japan.

^* To whom correspondence should be addressed. E-mail: nabemr{at}lmls.med.kyoto-u.ac.jp.

Background--Homozygous mutant mice with a defect of klotho gene expression (kl/kl) show multiple age-related disorders and premature death from unknown causes.

Methods and 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.

Key words: genetics • death, sudden • aging • sinoatrial node

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