Sema3a maintains normal heart rhythm through sympathetic innervation patterning
Sema3a maintains normal heart rhythm through sympathetic innervation patterning
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DOI：
10.1038/nm1570
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发表时间：
2007-05-01
期刊：
影响因子：
82.9
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Ieda, Masaki;Kanazawa, Hideaki;Fukuda, Keiichi
交感神经支配对有效的心脏功能至关重要。然而，决定心脏交感神经支配的密度和模式的发育和调节机制仍然不清楚，这种神经支配在心脏发生中的作用也不清楚。在这里，我们表明，神经化学排斥，Sema 3a，建立心脏交感神经支配模式。Sema 3a在早期胚胎的小梁层中大量表达，但在出生后仅限于浦肯野纤维，形成心外膜到内膜的透壁交感神经支配模式。Sema 3a（-/-）小鼠缺乏心脏交感神经支配梯度，并表现出星状神经节畸形，这导致了显着的窦性心动过缓，由于交感神经功能障碍。转基因小鼠（SemaTG）中Sema 3a的心脏特异性过表达与交感神经支配减少和心外膜-心内膜神经支配梯度衰减相关。SemaTG小鼠表现出猝死和室性心动过速的易感性，由于儿茶酚胺超敏性和动作电位持续时间的延长。我们的结论是，适当的心脏Sema 3a的表达需要交感神经支配模式，是心率控制的关键。
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.