Article abstract
Nature Medicine 13, 604 - 612 (2007)
Published online: 8 April 2007 | doi:10.1038/nm1570
Sema3a maintains normal heart rhythm through sympathetic innervation patterning
Masaki Ieda1,2, Hideaki Kanazawa1,2, Kensuke Kimura1, Fumiyuki Hattori1, Yasuyo Ieda1, Masahiko Taniguchi3, Jong-Kook Lee4, Keisuke Matsumura1,2, Yuichi Tomita1, Shunichiro Miyoshi2, Kouji Shimoda5, Shinji Makino1, Motoaki Sano1, Itsuo Kodama4, Satoshi Ogawa2 & Keiichi Fukuda1
Abstract
Sympathetic innervation is critical for effective cardiac function. However, the developmental and regulatory mechanisms determining the density and patterning of cardiac sympathetic innervation remain unclear, as does the role of this innervation in arrhythmogenesis. Here we show that a neural chemorepellent, Sema3a, establishes cardiac sympathetic innervation patterning. Sema3a is abundantly expressed in the trabecular layer in early-stage embryos but is restricted to Purkinje fibers after birth, forming an epicardial-to-endocardial transmural sympathetic innervation patterning. Sema3a-/- mice lacked a cardiac sympathetic innervation gradient and exhibited stellate ganglia malformation, which led to marked sinus bradycardia due to sympathetic dysfunction. Cardiac-specific overexpression of Sema3a in transgenic mice (SemaTG) was associated with reduced sympathetic innervation and attenuation of the epicardial-to-endocardial innervation gradient. SemaTG mice demonstrated sudden death and susceptibility to ventricular tachycardia, due to catecholamine supersensitivity and prolongation of the action potential duration. We conclude that appropriate cardiac Sema3a expression is needed for sympathetic innervation patterning and is critical for heart rate control.
- Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
- Cardiology Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
- Department of Biochemistry, Cancer Research Institute, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan.
- Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
- Laboratory Animal Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Correspondence to: Keiichi Fukuda1 e-mail: kfukuda@sc.itc.keio.ac.jp
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