Department of Pharmacology, Shiga University of Medical Science, Otsu, Shiga, Japan.
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
FASEB J. 2020 Sep;34(9):11624-11640. doi: 10.1096/fj.202000604R. Epub 2020 Jul 19.
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 (p75 , Ngfr) is increased in Nrdc LV due to the reduced ectodomain shedding of p75 . Importantly, the reduction of p75 rescued the abnormal innervation phenotype of Nrdc mice. Moreover, sympathetic neuron-specific, but not cardiomyocyte-specific deletion of Nrdc recapitulated the abnormal innervation patterning of Nrdc mice. In conclusion, neuronal nardilysin critically regulates cardiac sympathetic innervation and circulatory dynamics via modulation of p75 .
心脏交感神经支配对于循环动力学的调节至关重要。然而，神经支配模式的分子机制仍然难以捉摸。在这里，我们证明了脑啡肽酶（NRDC，Nrdc），一种外显子脱落的增强子，调节心脏交感神经支配。脑啡肽酶缺乏（Nrdc）小鼠表现出心脏发育不良、低血压、心动过缓和异常的交感神经支配模式。虽然野生型小鼠左心室（LV）的神经支配在心外膜下比心内膜下更密集，但 Nrdc 的 LV 缺乏这种极性，并且均匀且更丰富地被神经支配。在分子水平上，由于 p75 的外显子脱落减少，Nrdc 的 LV 中全长形式的 p75 神经生长因子受体（p75，Ngfr）增加。重要的是，p75 的减少挽救了 Nrdc 小鼠的异常神经支配表型。此外，交感神经元特异性而非心肌细胞特异性的 Nrdc 缺失重现了 Nrdc 小鼠的异常神经支配模式。总之，神经元脑啡肽酶通过调节 p75 来调节心脏交感神经支配和循环动力学。
