Nardilysin controls cardiac sympathetic innervation patterning through regulation of p75 neurotrophin receptor.
Nardilysin controls cardiac sympathetic innervation patterning through regulation of p75 neurotrophin receptor.
复制标题
Nardilysin 通过调节 p75 神经营养蛋白受体来控制心脏交感神经支配模式。
DOI：
10.1096/fj.202000604r
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发表时间：
2020
期刊：
影响因子：
4.8
通讯作者：
and Nishi E
中科院分区：
文献类型：
--
作者：
Ohno M;Nishi K;Hiraoka Y;Niizuma S;Matsuda S;Iwasaki H;Kimura K;and Nishi E
心脏交感神经支配在循环动力学的调节中起关键作用。然而，神经支配模式的分子机制尚不清楚。在这里，我们证明了nardilysin (NRDC， NRDC)，一种外域脱落的增强剂，调节心脏交感神经支配。Nardilysin - deficient （Nrdc - / -）小鼠表现为心脏发育不良、低血压、心动过缓和交感神经支配模式异常。野生型小鼠左心室（LV）在心内膜下的神经支配比在心内膜下的神经支配更密集，而Nrdc - / - LV缺乏这种极性，神经支配更为均匀和丰富。在分子水平上，由于p75NTR的外域脱落减少，nrdc−/−LV中p75神经营养因子受体（p75NTR,Ngfr）的全长形式增加。重要的是，p75ntr的减少挽救了nrdc - / -小鼠的异常神经支配表型。此外，nrdc - / -小鼠的交感神经元特异性缺失，而非心肌细胞特异性缺失再现了nrdc - / -小鼠的异常神经支配模式。综上所述，神经元溶钠素通过调节p75NTR对心脏交感神经支配和循环动力学起到关键作用。
Cardiac sympathetic innervation is critically involved in the regulation of circulatory dynamics. However, the molecular mechanism for the innervation patterning has remained elusive. Here, we demonstrate that nardilysin (NRDC,Nrdc), an enhancer of ectodomain shedding, regulates cardiac sympathetic innervation. Nardilysin‐deficient (Nrdc−/−) mice show hypoplastic hearts, hypotension, bradycardia, and abnormal sympathetic innervation patterning. While the innervation of left ventricle (LV) of wild‐type mice is denser in the subepicardium than in the subendocardium,Nrdc−/−LV lacks such a polarity and is uniformly and more abundantly innervated. At the molecular level, the full‐length form of p75 neurotrophin receptor (p75NTR,Ngfr) is increased inNrdc−/−LV due to the reduced ectodomain shedding of p75NTR. Importantly, the reduction of p75NTRrescued the abnormal innervation phenotype ofNrdc−/−mice. Moreover, sympathetic neuron‐specific, but not cardiomyocyte‐specific deletion ofNrdcrecapitulated the abnormal innervation patterning ofNrdc−/−mice. In conclusion, neuronal nardilysin critically regulates cardiac sympathetic innervation and circulatory dynamics via modulation of p75NTR.