Jugang Chen1, Dechun Yin1, Xiaojing He2, Meng Gao1, Yongsub Choi3, Guanghui Luo4, Haixing Wang1, Xiufen Qu5. 1. Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China. 2. Department of Neonatology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China. 3. Department of Internal Medicine, BronxCare Health System, NY, USA. 4. Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China. 5. Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: qxf0717@126.com.
Abstract
BACKGROUND: Sympathetic overactivation after acute myocardial infarction (AMI) contributes to ventricular arrhythmia (VA). Paraventricular nucleus (PVN) of the hypothalamus may play an important role on this context, however, the mechanisms remain unknown. In this study, we investigated whether inhibition of activated astrocytes in the PVN could reduce VA in rats with AMI. METHODS: The anesthetized rats were randomly divided into four groups of sham-operated, AMI, AMI + vehicle and AMI + fluorocitrate (FCA). Electrocardiogram was continuously recorded. RNA sequencing, sympathetic nerve activity (heart rate variability and norepinephrine levels) and ventricular electrical instability (ventricular effective refractory period and ventricular fibrillation inducibility) were measured. Furthermore, brain tissues were extracted to detect expression of inflammatory cytokines (IL-6, and TNF-α), astrocyte and neuro activation. RESULTS: RNA sequencing analysis showed that functions of differentially expressed genes in the PVN of AMI rats were significantly enriched in immune system- and neuroactive-related pathways, along with enhance expression of cytokines and Glial fibrillary acidic protein (GFAP). We further characterized that astrocytes were activated in PVN and intervention of activation astrocytes by FCA significantly inhibited sympathetic nerve activity and decreased the incidence of VA and ventricular electrical instability in rats with AMI. Moreover, FCA significantly attenuated neurons activation and downregulated expression of inflammatory cytokines in the PVN. CONCLUSIONS: Inhibition of activated astrocytes in the PVN could reduce VA occurrence and improve ventricular electrical instability in AMI rats by central neuro-immune pathway. These findings suggest that astrocytes are a potential target for prevention and treatment of VA complicating AMI.
BACKGROUND: Sympathetic overactivation after acute myocardial infarction (AMI) contributes to ventricular arrhythmia (VA). Paraventricular nucleus (PVN) of the hypothalamus may play an important role on this context, however, the mechanisms remain unknown. In this study, we investigated whether inhibition of activated astrocytes in the PVN could reduce VA in rats with AMI. METHODS: The anesthetized rats were randomly divided into four groups of sham-operated, AMI, AMI + vehicle and AMI + fluorocitrate (FCA). Electrocardiogram was continuously recorded. RNA sequencing, sympathetic nerve activity (heart rate variability and norepinephrine levels) and ventricular electrical instability (ventricular effective refractory period and ventricular fibrillation inducibility) were measured. Furthermore, brain tissues were extracted to detect expression of inflammatory cytokines (IL-6, and TNF-α), astrocyte and neuro activation. RESULTS: RNA sequencing analysis showed that functions of differentially expressed genes in the PVN of AMI rats were significantly enriched in immune system- and neuroactive-related pathways, along with enhance expression of cytokines and Glial fibrillary acidic protein (GFAP). We further characterized that astrocytes were activated in PVN and intervention of activation astrocytes by FCA significantly inhibited sympathetic nerve activity and decreased the incidence of VA and ventricular electrical instability in rats with AMI. Moreover, FCA significantly attenuated neurons activation and downregulated expression of inflammatory cytokines in the PVN. CONCLUSIONS: Inhibition of activated astrocytes in the PVN could reduce VA occurrence and improve ventricular electrical instability in AMI rats by central neuro-immune pathway. These findings suggest that astrocytes are a potential target for prevention and treatment of VA complicating AMI.