Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression - PubMed (original) (raw)

. 2004 Apr 13;109(14):1776-82.

doi: 10.1161/01.CIR.0000124224.48962.32. Epub 2004 Mar 22.

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

Affiliations

• PMID: 15037532
• DOI: 10.1161/01.CIR.0000124224.48962.32

Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression

Kyosuke Takeshita et al. Circulation. 2004.

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.

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.

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