This Article Full Text Full Text (PDF) All Versions of this Article: 109/14/1776    most recent 01.CIR.0000124224.48962.32v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takeshita, K. Articles by Nabeshima, Y.-i. Search for Related Content PubMed PubMed Citation Articles by Takeshita, K. Articles by Nabeshima, Y.-i. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Related Collections Animal models of human disease

(Circulation. 2004;109:1776-1782.)
© 2004 American Heart Association, Inc.

Basic Science Reports

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; 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.

Correspondence to Yo-ichi Nabeshima, MD, PhD, Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe cho, Sakyo-ku, Kyoto 606-8501, Japan. E-mail nabemr{at}lmls.med.kyoto-u.ac.jp

Received August 12, 2003; revision received December 3, 2003; accepted December 22, 2003.

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

This article has been cited by other articles:

				R. T. Alexander, T. E. Woudenberg-Vrenken, J. Buurman, H. Dijkman, B. C. J. van der Eerden, J. P.T.M. van Leeuwen, R. J. Bindels, and J. G. Hoenderop Klotho Prevents Renal Calcium Loss J. Am. Soc. Nephrol., November 1, 2009; 20(11): 2371 - 2379. [Abstract] [Full Text] [PDF]

				P. Liu, X. Bai, H. Wang, A. Karaplis, D. Goltzman, and D. Miao Hypophosphatemia-mediated hypotension in transgenic mice overexpressing human FGF-23 Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1514 - H1520. [Abstract] [Full Text] [PDF]

				M. S. Razzaque Does FGF23 toxicity influence the outcome of chronic kidney disease? Nephrol. Dial. Transplant., January 1, 2009; 24(1): 4 - 7. [Full Text] [PDF]

				A. Imura, Y. Tsuji, M. Murata, R. Maeda, K. Kubota, A. Iwano, C. Obuse, K. Togashi, M. Tominaga, N. Kita, et al. {alpha}-Klotho as a Regulator of Calcium Homeostasis Science, June 15, 2007; 316(5831): 1615 - 1618. [Abstract] [Full Text] [PDF]

				Y. Haruna, N. Kashihara, M. Satoh, N. Tomita, T. Namikoshi, T. Sasaki, T. Fujimori, P. Xie, and Y. S. Kanwar Amelioration of progressive renal injury by genetic manipulation of Klotho gene PNAS, February 13, 2007; 104(7): 2331 - 2336. [Abstract] [Full Text] [PDF]

				Y.-i. Nabeshima Toward a better understanding of klotho. Sci. Aging Knowl. Environ., March 22, 2006; 2006(8): pe11 - pe11. [Abstract] [Full Text]

				D. E. Arking, G. Atzmon, A. Arking, N. Barzilai, and H. C. Dietz Association Between a Functional Variant of the KLOTHO Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity Circ. Res., March 4, 2005; 96(4): 412 - 418. [Abstract] [Full Text] [PDF]

				O. Vonend, T. Apel, K. Amann, L. Sellin, J. Stegbauer, E. Ritz, and L. C. Rump Modulation of gene expression by moxonidine in rats with chronic renal failure Nephrol. Dial. Transplant., September 1, 2004; 19(9): 2217 - 2222. [Abstract] [Full Text] [PDF]