Inhibition of Notch signaling pathway attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats post-myocardial infarction.
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.
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Jie
J
Yin
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Hesheng
H
Hu
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Xiaolu
X
Li
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Mei
M
Xue
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Wenjuan
W
Cheng
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Ye
Y
Wang
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Yongli
Y
Xuan
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Xinran
X
Li
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Na
N
Yang
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
Yugen
Y
Shi
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China yansuhua296@163.com.
Suhua
S
Yan
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D006321:Heart / Q000294:innervation*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004151:Dipeptides; C000594089:IL1B protein, rat; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor
Notch; macrophage; myocardial infarction; nerve growth factor; sympathetic sprouting