Inhibition of Notch signaling pathway attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats post-myocardial infarction

Abstract

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

Macrophage and nerve interaction in endometriosis

“…The necessary role of the macrophage is enhanced in studies that focus on sympathetic sprouting. The inhibition of the Notch signaling pathway could attenuate NGF-induced sympathetic nerve sprouting by polarizing the macrophages toward M2 phenotype [86]. Accordingly, we can speculate that there exists a similar association between macrophage polarization and neurogenesis in endometriosis.…”

A novel sympathetic neuronal GABAergic signalling system regulates NE release to prevent ventricular arrhythmias after acute myocardial infarction

“…54 During this experiment, an animal biological function experiment system (BL-420S, TaiMeng, China) was used to monitor the electrocardiogram (ECG). Then, the heart was exposed through pericardiotomy.…”

“…54,61 After monitoring the surface ECG, a programmed stimulation protocol was performed using electrodes implanted on the epicardial surface of the LV. The protocol used for the programmed electrical stimulation was performed as previously reported.…”

“…The left anterior descending coronary artery was ligated 2 mm from its origin between the pulmonary artery conus and left atrium to induce MI as previously described with 6/0 silk sutures. 54 During this experiment, an animal biological function experiment system (BL-420S, TaiMeng, China) was used to monitor the electrocardiogram (ECG). MI was confirmed by ST elevation on a surface ECG and stiff movement of the left ventricle (LV).…”

“…The protocol used for the programmed electrical stimulation was performed as previously reported. 54,61 After monitoring the surface ECG, a programmed stimulation protocol was performed using electrodes implanted on the epicardial surface of the LV. Programmed electrical stimulation was performed to induce VAs as follows: eight paced beats at a cycle length of 120 ms (S1) were applied, followed by one to three extrastimuli (S2, S3 and S4) at shorter coupling intervals.…”