Microglial Mincle receptor in the PVN contributes to sympathetic hyperactivity in acute myocardial infarction rat

Abstract

Malignant ventricular arrhythmias (VAs) following myocardial infarction (MI) is a lethal complication resulting from sympathetic nerve hyperactivity. Numerous evidence have shown that inflammation within the paraventricular nucleus (PVN) participates in sympathetic hyperactivity. Our aim was to explore the role of Macrophage‐inducible C‐type lectin (Mincle) within the PVN in augmenting sympathetic activity following MI,and whether NOD‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome/IL‐1β axis is involved in this activity. MI was induced by coronary artery ligation. Mincle expression localized in microglia within the PVN was markedly increased at 24 hours post‐MI together with sympathetic hyperactivity, as indicated by measurement of the renal sympathetic nerve activity (RSNA) and norepinephrine (NE) concentration. Mincle‐specific siRNA was administrated locally to the PVN, which consequently decreased microglial activation and sympathetic nerve activity. The MI rats exhibited a higher arrhythmia score after programmed electric stimulation than that treated with Mincle siRNA, suggesting that the inhibition of Mincle attenuated foetal ventricular arrhythmias post‐MI. The underlying mechanism of Mincle in sympathetic hyperactivity was investigated in lipopolysaccharide (LPS)‐primed naïve rats. Recombinant Sin3A‐associated protein 130kD (rSAP130), an endogenous ligand for Mincle, induced high levels of NLRP3 and mature IL‐1β protein. PVN‐targeted injection of NLRP3 siRNA or IL‐1β antagonist gevokizumab attenuated sympathetic hyperactivity. Together, the data indicated that the knockdown of Mincle in microglia within the PVN prevents VAs by attenuating sympathetic hyperactivity and ventricular susceptibility, in part by inhibiting its downstream NLRP3/IL‐1β axis following MI. Therapeutic interventions targeting Mincle signalling pathway could constitute a novel approach for preventing infarction injury.

Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation

“…However, the underlying upstream mechanism remains unclear. A previous study reported that the NLRP3–IL‐1β axis contributed to sympathetic hyperactivity and myocardial infarction‐induced VA (Wang et al., 2019). Thus, we checked the NLRP3–IL‐1β axis in mice with HFpEF, with or without MD1 deletion, by assessing the protein levels of NLRP3, caspase‐1 and IL‐1β.…”

“…The inflammatory response has been demonstrated to regulate sympathetic activity (Wei, Yu, Zhang, & Felder, 2015). Previous studies reported that inhibition of inflammatory response could suppress sympathetic hyperactivity and prevent VA (Kang et al., 2009; Wang et al., 2019). To explain the above findings, we hypothesize that HFpEF induces an inflammatory response and that an accumulation of cytokines contributes to the sympathetic hyperactivity and facilitates VA.…”

“…The NLRP3 inflammasome has been reported to serve as an important inflammatory mediator in several cardiovascular diseases (Kawaguchi et al., 2011; Sandanger et al., 2013; Wang, Qu, Zhao, & Chang, 2004). A previous study showed that inhibition of the NLRP3–IL‐1β axis could suppress sympathetic hyperactivity and, ultimately, prevent myocardial infarction‐induced VA (Wang et al., 2019). Therefore, activation of NLRP3–IL‐1β‐mediated cardiac sympathetic hyperactivity might also be involved in HFpEF‐induced VA.…”

Ambiguity about Splicing Factor 3b Subunit 3 (SF3B3) and Sin3A Associated Protein 130 (SAP130)

“…The protein was erroneously referred to as Sin3A associated protein 130 (SAP130), its function was described as histone deacetylase, and ultimately qPCR primers and an antibody against SAP130 were used in research on SF3B3 [ 1 , 2 , 3 ]. Furthermore, we cannot confirm that reagents used in five research articles were indeed for SF3B3, as the corresponding authors did not provide the missing reagent information [ 12 , 17 , 20 , 21 , 22 ]. The results in the former three papers should be validated, and the materials in the latter five papers should be checked to make sure they were designed for SF3B3 and not for SAP130.…”

Parental Renovascular Hypertension-Induced Autonomic Dysfunction in Male Offspring Is Improved by Prenatal or Postnatal Treatment With Hydrogen Sulfide

“…Activation of the NLRP3 inflammasome promoted the secretion of inflammatory cytokines IL-1β. IL-1β is recognized as a key trigger of inflammation and is involved in sympathetic hyperactivity (Wang et al, 2019; Yin et al, 2019). Furthermore, the activation of reactive oxygen species (ROS) participates in the activation of NLRP3 inflammasome (Gross et al, 2016).…”