High mobility group box-1 in hypothalamic paraventricular nuclei attenuates sympathetic tone in rats at post-myocardial infarction
Abstract
Background: Inflammation is associated with increased sympathetic drive in cardiovascular diseases. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity at post-myocardial infarction (MI). High mobility group box-1 (HMGB1) exhibits inflammatory cytokine like activity in the extracellular space. Inflammation is associated with increased sympathetic drive in cardiovscular diseases. However, the role of HMGB1 in sympathetic nerve activity at post-MI remains unknown. The aim of the present study is to determine the role and mechanism of HMGB1 in the PVN, in terms of sympathetic activity and arrhythmia after MI.
Methods: Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce MI. Anti-HMGB1 polyclonal antibody or control IgG was bilaterally microinjected into the PVN (5 μL every second day for seven consecutive days). Then, renal sympathetic nerve activity (RSNA) was recorded. The association between ventricular arrhythmias (VAs) and MI was evaluated using programmed
electrophysiological stimulation. After performing electrophysiological experiments in vivo, immunohistochemistry was used to detect the distribution of HMGB1, while Western blot was used to detect the expression of HMGB1 and p-ERK in the PVN of MI rats.
Results: HMGB1 and p-ERK were upregulated in the PVN in rats at post-MI. Moreover, bilateral PVN microinjection of anti-HMGB1 polyclonal antibody reversed the expression of HMGB1 and p-ERK, and consequently decreased the baseline RSNA and inducible VAs, when compared to those in sham rats.
Conclusions: These results suggest that MI causes the translocation of HMGB1 in the PVN, which leads to sympathetic overactivation through the ERK1/2 signaling pathway. The bilateral PVN microinjection of anti-HMGB1 antibody can be an effective therapy for MI-induced arrhythmia.
Keywords: HMGB1ERKhypothalamic paraventricular nucleussympathetic nervemyocardial infarction
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