Abstract P159: Neural Inflammation Results in Cardiac Sympathetic Afferent Sensitization in Post-Myocardial Infarction Rats

Abstract

Sympatho-excitation is a hallmark of the chronic heart failure (CHF) state. The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the elevated sympathetic tone in CHF. However, the mechanisms underlying the CSAR sensitization have not been fully discovered. We hypothesized that myocardial infarction (MI) will trigger a neuro-inflammatory cascade that includes macrophage activation in thoracic dorsal root ganglia (DRG), which results in cardiac spinal afferent sensitization. Our immunofluorescence data ( Figure 1 ) demonstrated that, the number of Iba-1-positive (a macrophage marker) cells in T1-T4 DRGs of MI rats was significantly increased at 1 week and lasted at least 8 weeks post MI. RNA-seq analysis data in T1-T4 DRGs of MI rats also showed upregulated mRNA expressions of several macrophage-activation related genes such as IRF7, RGD1309362, slfn4 and lfit1. In the in vitro experiments, after the 50B11 DRG cells were co-cultured with LPS-pretreated BV2 cells (activated microglia/macrophage), the protein expressions of voltage-gated potassium channel isoforms (Kv1.4, Kv4.2, Kv4.3 and Kv3.4) were largely reduced, which explains how macrophage activation cause DRG neuronal sensitization. Lastly, our data showed that 4-week treatment with minocycline (a macrophage inhibitor, 40 mg/kg/day) via drinking water markedly reduced the enhanced CSAR in the post-MI rats (MAP, 30.2±2.6 vs. 18.0±1.9 mmHg, n=6, p<0.01; HR, 43.5±5.5 vs. 12.5±2.0 bpm, n=6, p<0.01; RSNA, 169.2±19.5 vs. 77.8±4.6% baseline, n=6, p<0.01). These data suggested that macrophage infiltration in sensory ganglia contributes to the sensitization of the CSAR in the post-MI state.