Inhibition of Notch signaling pathway attenuates sympathetic hyperinnervation

Abstract

21 Background: Inflammation-dominated sympathetic sprouting adjacent to the necrotic 22 region following myocardial infarction (MI) has been implicated in the etiology of 23 arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain 24 to be elucidated. Although being a key immune mediator, the role of the Notch has yet to be 25 explored. 26 Objective: We investigated whether Notch regulates macrophage responses to 27 inflammation and affects cardiac sympathetic reinnervation in rats undergoing MI. 28 Methods and Results: MI was induced by coronary artery ligation. A high level of NICD 29 was observed in the macrophages that infiltrated the infarct area at 3 days post-MI. The 30 administration of the Notch inhibitor 31 N-N-(3,5-difluorophenacetyl-l-alanyl)-S-phenylglycine-t-butyl ester (DAPT) (i.v. 30 minutes 32 before MI and then daily until sacrifice) decreased the number of macrophages and 33 significantly increased the M2 macrophage activation profile in the early stages as well as 34 attenuated the expression of nerve growth factor (NGF). Eventually, NGF-induced 35 sympathetic hyperinnervation was blunted, as assessed by the immunofluorescence of 36 tyrosine hydroxylase (TH). At 7 days post-MI, the arrhythmia score of programmed electric 37 stimulation in the vehicle-treated infarcted rats was higher than that in rats treated with DAPT. 38 Further deterioration in cardiac function and decreases in the plasma levels of TNF-α and 39 IL-1β were also detected. In vitro studies revealed that LPS/IFN-γ upregulated the surface 40 expression of NGF in M1 macrophages in a Notch-dependent manner. Conclusions: Notch 41 inhibition during the acute inflammatory response phase is associated with the 42 downregulation of NGF, probably through a macrophage-dependent pathway, thus 43 preventing the process of sympathetic hyperinnervation. 44

Cite this paper

@inproceedings{Yin2015InhibitionON, title={Inhibition of Notch signaling pathway attenuates sympathetic hyperinnervation}, author={Jie Yin and Hesheng Hu and Xiaolu Li and Mei Xue and Wenjuan Cheng and Ye Wang and Yongli Xuan and Xinran Li and Yugen Shi and Suhua Yan}, year={2015} }