BackgroundWith chronic ischemia after myocardial infarction, the resulting scar tissue result in electrical and structural remodeling vulnerable to an arrhythmogenic substrate. The cholinergic anti‐inflammatory pathway elicited by vagal nerve via α7 nicotinic acetylcholine receptors (α7‐nAChR) can modulate local and systemic inflammatory responses. Here, we aimed to clarify a novel mechanism for the antiarrhythmogenic properties of vagal nerve during the ischemic cardiomyopathy (ICM).Methods and ResultsLeft anterior descending artery of adult male Sprague‐Dawley rats was ligated for 4 weeks to develop ICM. Western blot revealed that eliciting the cholinergic anti‐inflammatory pathway by nicotine treatment showed a significant reduction in the amounts of collagens, cytokines, and other inflammatory mediators in the left ventricular infarcted border zone via inhibited NF‐κB activation, whereas it increased the phosphorylated connexin 43. Vagotomy inhibited the anti‐inflammatory, anti‐fibrosis, and anti‐arrhythmogenic effect of nicotine administration. And immunohistochemistry confirmed that the nicotine administration‐induced increase of connexin 43 was located in intercellular junctions. Furthermore nicotine treatment suppressed NF‐κB activation in lipopolysaccharide‐stimulated RAW264.7 cells, and α‐bungarotoxin (an α7‐nAChR selective antagonist) partly inhibited the nicotine‐treatment effect. In addition, 4‐week nicotine administration slightly improved the cardiac function, increased cardiac parasympathetic tone, decreased the prolonged QTc, and decreased the arrhythmia score of programmed electric stimulation‐induced ventricular arrhythmia.ConclusionsEliciting the cholinergic anti‐inflammatory pathway exerts anti‐arrhythmogenic effects against ICM‐induced ventricular arrhythmia accompanied by downregulation of cytokines, downgenerating of collagens, decrease in sympathetic/parasympathetic ratio, and prevention of the loss of phosphorylated connexin 43 during ICM. Our findings may suggest a promising therapy for the generation of ICM‐induced ventricular arrhythmia by eliciting the cholinergic anti‐inflammatory pathway.
Our previous studies have reported that agonist of α7 nicotinic acetylcholine receptors prevented electrophysiological dysfunction of rats with ischaemic cardiomyopathy (ICM) by eliciting the cholinergic anti‐inflammatory pathway (CAP). Adenosine monophosphate‐activated protein kinase (AMPK) signalling is widely recognized exerting cardioprotective effect in various cardiomyopathy. Here, we aimed to investigate whether the protective effects of the CAP are associated with AMPK signalling in ICM. In vivo, coronary artery of rats was ligated for 4 weeks to induce the ICM and then treated with PNU‐282987 (CAP agonist) and BML‐275 dihydrochloride (AMPK antagonist) for 4 weeks. In vitro, primary macrophages harvested from rats were induced inflammation by Lipopolysaccharide (LPS) treatment and then treated with PNU‐282987 and BML‐275 dihydrochloride. In vivo, exciting CAP by PUN‐282987 elicited an activation of AMPK signalling, alleviated ventricular remodeling, modified the cardiac electrophysiological function, reduced the cardiac expression of collagens and inflammatory cytokines and maintained the integrity of ultrastructure in the ischemic heart. However, the benefits of CAP excitation were blunted by AMPK signaling antagonization. In vitro, excitation of the CAP was observed inhibiting the nuclear transfer of NF‐κB p65 of macrophages and promoting the transformation of Ly‐6C high macrophages into Ly‐6C low macrophages. However, inhibiting AMPK signalling by BML‐275 dihydrochloride reversed the CAP effect on LPS‐treated macrophages. Finally, our findings suggest that eliciting the CAP modulates the inflammatory response in ICM through regulating AMPK signalling.
With the chronic ischemia persisting after acute myocardial infarction, the accompanying low-degree inflammation and subsequent fibrosis result in progression of cardiac remodeling and heart failure. Recently, Sodium Houttuyfonate (SH), a pure compound extracted from Houttuynia cordata, has been confirmed exerting anti-inflammatory and anti-fibrotic effects under diseased situations. Here, we aimed to investigate whether SH could reverse the cardiac remodeling post-myocardial infarction by alleviating cardiac inflammation and fibrosis. Left anterior descending coronary artery of adult male Sprague-Dawley rats was ligated to elicit myocardial infarction. Low and high dose of SH was administered by oral gavage for four consecutive weeks post-myocardial infarction. Long-term SH treatment decreased heart rate, heart weight/ body weight (HW/BW), and left ventricle weight/body weight (LVW/BW), reduced cardiac expression of brain natriuretic peptide (BNP), improved left ventricular heart function, and ameliorated the histopathological changes caused by myocardial infarction. Western blotting revealed the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), transforming growth factor-β (TGF-β), collagen I, and collagen III of the infarcted ventricle were reduced by SH treatment. Meanwhile, we found that SH treatment post-myocardial infarction activated AMP-activated protein kinase (AMPK) and suppressed nuclear factor-κB p65 (NF-κB p65). Furthermore, on H9C2 cells induced hypoxic injury with cobalt chloride (CoCl2), the reduction of inflammatory cytokines (IL-6, TNF-α, and TGF-β), activation of AMPK, and suppression of NF-κB p65 were also observed by SH treatment. However, transfection of H9C2 with AMPKα siRNA blunted the suppression of NF-κB p65 and inflammatory cytokines (IL-6, TNF-α, and TGF-β) by SH post-hypoxia. Taken together, these findings suggested that long-term administration of SH post-myocardial infarction reduced cardiac inflammatory and fibrotic responses, and reversed cardiac remodeling process. The underlying mechanism may be activating AMPK and suppressing NF-κB pathway.
MicroRNAs (miR) are a class of non-coding endogenous RNA molecules that suppress the translation of protein-coding genes by destabilizing target mRNAs. The MiR-574-5p has been reported to be involved in the several types of cancer. However, the expression of miR-574-5p and its mechanism in nasopharyngeal carcinoma (NPC) remain unclear. We found that the expression level of miR-574-5p was significantly increased in the NPC cell lines. We further demonstrated that Forkhead box N3 (FOXN3) was a target gene of miR-574-5p. FOXN3 overexpression and inhibition reversed the promoting or suppressing effect, respectively, of NPC cell proliferation, migration and invasion caused by miR-574-5p. Furthermore, miR-574-5p enhanced the β-catenin and TCF4 protein expression by repressing FOXN3 expression, resulting in the activation of the Wnt/β-catenin signaling pathway, but the activity of the Wnt/β-catenin signaling pathway was inhibited by a miR-574-5p inhibitor or FOXN3 overexpression, which reversed the effect of miR-574-5p. Wound-healing and Transwell assays also showed that miR-574-5p promotes the cell migration and invasion of NPC cells, whereas the promoting effect of miR-574-5p was also reversed by a miR-574-5p inhibitor or FOXN3 overexpression. Collectively, these data suggested that miR-574-5p promotes NPC cell proliferation, migration, and invasion at least partly by targeting the FOXN3/Wnt/β-Catenin signaling pathway.
Hypothesis: Cochlear microphonic recorded at ear canal (CM-EC) can be a substitute for the one recorded at round window (CM-RW).Background: Almost all clinics do not measure tone-burst evoked CM due to technical difficulty although it can provide more information than click evoked CM. Moreover, clinicians like the CM-EC more than that measured at CM-RW because CM-EC is non-invasive. There is difference between CM-RW and CM-EC, for example, CM-EC is less prominent than CM-RW, therefore, studying tone-burst evoked CM-EC and its relationship with CM-RW are highly significant and can promote the clinical application of CM-EC.Method: Nine guinea pigs were randomly allocated into three groups, group 1 was not exposed to noise, called normal control. group 2 and group 3 were exposed to the low-(0.5-2 kHz) and high-frequency band-noise (6-8 kHz) at 120 dB SPL for 1 h, respectively. It was difficulty to record low-frequency CM due to severe environmental interruption, in current study the recording technology of tone-burst evoked CM
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.