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

被引:168
作者
Takeshita, K
Fujimori, T
Kurotaki, Y
Honjo, H
Tsujikawa, H
Yasui, K
Lee, JK
Kamiya, K
Kitaichi, K
Yamamoto, K
Ito, M
Kondo, T
Iino, S
Inden, Y
Hirai, M
Murohara, T
Kodama, I
Nabeshima, Y
机构
[1] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Sakyo Ku, Kyoto 6068501, Japan
[2] Nagoya Univ, Grad Sch Med, Dept Cardiol, Nagoya, Aichi, Japan
[3] Nagoya Univ, Environm Med Res Inst, Nagoya, Aichi 464, Japan
[4] Nagoya Univ, Dept Hlth Med, Nagoya, Aichi, Japan
[5] Nagoya Univ, Grad Sch Med, Dept Mol Med & Clin Sci, Nagoya, Aichi, Japan
[6] Nagoya Univ Hosp, Div Pathol, Nagoya, Aichi, Japan
关键词
genetics; death; sudden; aging; sinoatrial node;
D O I
10.1161/01.CIR.0000124224.48962.32
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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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收藏
页码:1776 / 1782
页数:7
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