Subthreshold Splenic Nerve Stimulation Prevents Myocardial Ischemic Injury Via Downregulating CXCL17 and CCR2

Background: The clinical outcomes following a myocardial ischemia-reperfusion (I/R) injury are strongly associated with the intensity and duration of inflammation and the splenic nerve (SpN) is indispensable for the anti-inflammatory reflex. Objectives We aimed to investigate whether splenic nerve stimulation (SpNS) plays a cardioprotective role in myocardial ischemic injury and the potential underlying mechanism.Methods: The intensity of SpNS having no influence on heart rate was tested and used as the subthreshold stimulus. Subthreshold SpNS was performed with continuous-mode stimulation for 1 hour before myocardial ischemia-reperfusion (I/R) injury and chronic MI. After 72 hours of reperfusion and 4 weeks post-MI, samples were collected for analysis.Results: The activity of the SpN and splenic concentrations of cholinergic anti-inflammatory pathways (CAP)-related neurotransmitters were significantly increased by SpNS. Compared with I/R treatment alone, subthreshold SpNS significantly reduced the infarct size, proinflammatory response, oxidative stress and sympathetic tone after myocardial I/R injury. In the chronic MI model, left ventricular systolic function was enhanced and cardiac remodeling was inhibited by subthreshold SpNS. RNA-sequencing analysis and verification showed subthreshold SpNS downregulated CXCL17 and CCR2. Administration of CCR2 antagonist promoted the cardioprotective effect of subthreshold SpNS.Conclusions: Subthreshold SpNS ameliorates the myocardial damage, inflammatory response and cardiac remodeling induced by myocardial ischemic injury through activating CAP and downregulating CXCL17 and CCR2. Splenic nerve stimulation therapy provides a potential therapeutic strategy for treatment of myocardial ischemic injury though neuroimmunoregulation.