?1 Adrenoceptors Activation Promotes Macrophages Expressing NGF Via The Notch Pathway After MI

Background:Acute myocardial infarction(MI)is one of the most serious coronary heart disease,which seriously threatens human survival and health.Ventricular arrhythmia is the main cause of early death in patients with MI.Sympathetic nerve remodeling after myocardial infarction plays an important role in the occurrence of ventricular arrhythmia and sudden death.Studies have shown that after myocardial infarction,the concentration of norepinephrine in myocardial infarction peripheral area significantly increased,and consistent with sympathetic remodeling.This suggests that local catecholamines are rapidly secreted after myocardial infarction and remain at high levels.Beta-adrenergic receptor blocker-related studies have shown that metoprolol and carvedilol can improve sympathetic nerve remodeling after myocardial infarction,reduce susceptibility to ventricular arrhythmia.These findings suggest that elevated catecholamine can promote cardiac sympathetic nerve proliferation,but its role and mechanism needs further elucidation.Rapid and sustained up-regulation of nerve growth factor(NGF)in infarcted myocardium is the key to cardiac nerve regeneration and sympathetic nerve remodeling.Macrophages are the main source of NGF and play a decisive role in the process of sympathetic nerve remodeling after myocardial infarction.Results published by Flierl and Nguyen in Nature,respectively,show that adrenergic receptors are present on macrophage membranes and that adrenergic blockers suppress the production of multiple macrophage-derived inflammatory cytokines.During the process of sympathetic nerve remodeling after myocardial infarction,NGF is almost accompanied by increased expression of inflammatory cytokines.But whether catecholamines can promote macrophage expression of NGF is not clear.Some studies have done rat myocardial infarction model and found that inhibition of Notch pathway using DAPT can inhibit M1 macrophage release of NGF.These findings suggest that the notch pathway is involved in the release of NGF from macrophages,but its relationship with catecholamines remains unclear.Objective:Therefore,we explored the effect of epinephrine on lipopolysaccharide-induced NGF expression by macrophages and explored its mechanism of action.Method:Dose-and time-dependent effects of epinephrine onNGF expression from macrophage RAW264.7 were evaluated after LPS activation.We added different adrenergic blockers to explore the receptor subtypes that promote NGF expression.We also inhibited the Notch receptor using the y-secretase inhibitor DAPT to investigate whether the Notch pathway plays a role in the mechanism of action of epinephrine on LPS-induced macrophage responses.Results:Our results showed that epinephrine pretreatment(0.01nmol/mL)for 2 hours significantly promoted the expression of NGF by LPS-induced macrophages,and both metoprolol,a ?1-receptor blocker,and DAPT,a Notch pathway inhibitor,significantly inhibited this process.Conclusion:In this study,we found that:1.Low-dose epinephrine pretreatment of macrophages can significantly promote LPS-mediated macrophage expression of NGF.2.?1 adrenoceptors enhances the secretion of NGF from LPS-induced macrophage RAW264.7.3.The Notch pathway is involved in the process by which epinephrine promotes the expression of NGF.