Downregulation of CCR2 reduces ventricular remodeling after myocardial infarction by splenic nerve neuromodulation in acute and chronic rat models

Objectives: Pathological remodeling after myocardial infarction (MI) confers the development of heart failure. Our prior research has indicated that splenic nerve neuromodulation mitigates myocardial ischemia-reperfusion injury (IRI) by reducing levels of proinflammatory factors. This study aims to explore the potential therapeutic benefits of splenic nerve neuromodulation in MI and the underlying mechanism. Methods: Splenic nerve neuromodulation was performed through electrical splenic nerve stimulation (SpNS). In the acute myocardial IRI model, post-mortem analyses encompassed RNA sequencing and a range of molecular biology techniques, with the application of CCR2 antagonists (RS-504393) to inhibit the CCR2. In the chronic MI model, rats underwent echocardiographic assessment four weeks post-MI, after which tissues were harvested. Results: In the acute IRI model, the negative regulation of chemokines production pathway was enriched by RNAseq, and SpNS reduced the levels of CCR2, CCL2, and CCL7. The administration of RS-504393 decreased cardiomyocyte apoptosis, reduced myocardial damage, and lowered proinflammatory cytokines levels following myocardial IRI. Additionally, SpNS was shown to inhibit oxidative stress, proinflammatory cytokine levels, and cardiac collagen deposition, as observed four weeks post-MI. SpNS also restrained sympathetic nerve remodeling and improved left ventricular function, in part by downregulating CCR2 in the chronic MI model. Conclusions: SpNS demonstrated significant improvements in cardiac function, reductions of cardiac remodeling and inhibitions of excessive sympathetic activation in the chronic MI model by downregulation of CCR2. Our study provides novel evidence that splenic nerve neuromodulation may serve as a potential therapeutic intervention in MI patients.