Colchicine prevents atrial fibrillation promotion by inhibiting IL-1β-induced IL-6 release and atrial fibrosis in the rat sterile pericarditis model

Wu, Qiongfeng; Liu, Huixia; Liao, Jie; Zhao, Ning; Tse, Gary; Han, Bin; Chen, Lei; Huang, Zhengrong; Du, Yumin

doi:10.1016/j.biopha.2020.110384

Cited by 59 publications

(41 citation statements)

References 28 publications

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“…Moreover, IL-6 is early upregulated in the atria of rat and canine sterile pericarditis (SP), which are animal models of POAF ( 2 – 5 ). We found that IL-6 predisposes to atrial fibrosis and fibrillation by inducing cardiac fibroblast activation in SP rats ( 3 , 4 ), which is further confirmed by Liu et al. ( 6 ).…”

Section: Introductionsupporting

confidence: 87%

Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats

et al. 2021

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Pre-existing Ca2+ handling abnormalities constitute the arrhythmogenic substrate in patients developing postoperative atrial fibrillation (POAF), a common complication after cardiac surgery. Postoperative interleukin (IL)-6 levels are associated with atrial fibrosis in several animal models of POAF, contributing to atrial arrhythmias. Here, we hypothesize that IL-6-mediated-Ca2+ handling abnormalities contribute to atrial fibrillation (AF) in sterile pericarditis (SP) rats, an animal model of POAF. SP was induced in rats by dusting atria with sterile talcum powder. Anti-rat-IL-6 antibody (16.7 μg/kg) was administered intraperitoneally at 30 min after the recovery of anesthesia. In vivo electrophysiology, ex vivo optical mapping, western blots, and immunohistochemistry were performed to elucidate mechanisms of AF susceptibility. IL-6 neutralization ameliorated atrial inflammation and fibrosis, as well as AF susceptibility in vivo and the frequency of atrial ectopy and AF with a reentrant pattern in SP rats ex vivo. IL-6 neutralization reversed the prolongation and regional heterogeneity of Ca2+ transient duration, relieved alternans, reduced the incidence of discordant alternans, and prevented the reduction and regional heterogeneity of the recovery ratio of Ca2+ transient. In agreement, western blots showed that IL-6 neutralization reversed the reduction in the expression of ryanodine receptor 2 (RyR2) and phosphorylated phospholamban. Acute IL-6 administration to isolated rat hearts recapitulated partial Ca2+ handling phenotype in SP rats. In addition, intraperitoneal IL-6 administration to rats increased AF susceptibility, independent of fibrosis. Our results reveal that IL-6-mediated-Ca2+ handling abnormalities in SP rats, especially RyR2-dysfunction, independent of IL-6-induced-fibrosis, early contribute to the development of POAF by increasing propensity for arrhythmogenic alternans.

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Section: Introductionsupporting

confidence: 87%

Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats

et al. 2021

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“…Again, GSK2193874 treatment attenuated all the effects above ( Figures 5C, 5D). We previously found that the infiltration of immune cells was increased significantly in the atria from SP rats (19). Here we observed the number of MPO+ cells (neutrophil) and CD68+ cells (macrophages) was reduced after GSK2193874 treatment (P < 0.01 in MPO+ and P < 0.001 in CD68+ vs. vehicle, Supplemental Figure 8).…”

Section: Trpv4 Antagonist Gsk2193874 Reduces Interstitial Fibrosis Insupporting

confidence: 63%

TRPV4 blockade suppresses atrial fibrillation in sterile pericarditis rats

Liao¹,

Wu²,

Cheng³

et al. 2020

JCI Insight

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Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 d before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch-clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K + currents (IK), reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways, and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevents abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats, and, therefore, might be a promising strategy to treat AF, particularly post-operative AF.

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“…Recently, clinical proofs have highlighted the mechanistic link between the expression level of IL-6 and the development and prognostic of AF ( 52 ), the results suggest a declined expression of IL-6 may spur a lower incidence of AF ( 53 ), further mechanism studies have illustrated that the mutation of IL-6 and inflammatory reactions related to IL-6 are pivotal in the progress of atrial remodeling, which is one of the cores of the development of AF ( 54 – 57 ). Similarly, recent studies of rats suggested the declined release of IL-6 is related to the reduction of atrial fibrosis and a lower incidence of AF ( 58 , 59 ). ACE is one of the critical regulators of systemic vascular resistance, blood volume, and cardiovascular homeostasis.…”

Section: Discussionmentioning

confidence: 86%

Potential Mechanism of Dingji Fumai Decoction Against Atrial Fibrillation Based on Network Pharmacology, Molecular Docking, and Experimental Verification Integration Strategy

Liang

Wen

et al. 2021

Front. Cardiovasc. Med.

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Background: Dingji Fumai Decoction (DFD), a traditional herbal mixture, has been widely used to treat arrhythmia in clinical practice in China. However, the exploration of the active components and underlying mechanism of DFD in treating atrial fibrillation (AF) is still scarce.Methods: Compounds of DFD were collected from TCMSP, ETCM, and literature. The targets of active compounds were explored using SwissTargetPrediction. Meanwhile, targets of AF were collected from DrugBank, TTD, MalaCards, TCMSP, DisGeNET, and OMIM. Then, the H-C-T-D and PPI networks were constructed using STRING and analyzed using CytoNCA. Meanwhile, VarElect was utilized to detect the correlation between targets and diseases. Next, Metascape was employed for systematic analysis of the mechanism of potential targets and protein complexes in treating AF. AutoDock Vina, Pymol, and Discovery Studio were applied for molecular docking. Finally, the main findings were validated through molecular biology experiments.Results: A total of 168 active compounds and 1,093 targets of DFD were collected, and there were 89 shared targets between DFD and AF. H-C-T-D network showed the relationships among DFD, active compounds, targets, and AF. Three functional protein complexes of DFD were extracted from the PPI network. Further systematic analysis revealed that the regulation of cardiac oxidative stress, cardiac inflammation, and cardiac ion channels were the potential mechanism of DFD in treating AF. Addtionally, molecular docking verified the interactions between active compounds and targets. Finally, we found that DFD significantly increased the level of SIRT1 and reduced the levels of ACE, VCAM-1, and IL-6.Conclusions: DFD could be utilized in treating AF through a complicated mechanism, including interactions between related active compounds and targets, promoting the explanation and understanding of the molecular biological mechanism of DFD in the treatment of AF.

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Colchicine prevents atrial fibrillation promotion by inhibiting IL-1β-induced IL-6 release and atrial fibrosis in the rat sterile pericarditis model

Cited by 59 publications

References 28 publications

Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats

Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats

TRPV4 blockade suppresses atrial fibrillation in sterile pericarditis rats

Potential Mechanism of Dingji Fumai Decoction Against Atrial Fibrillation Based on Network Pharmacology, Molecular Docking, and Experimental Verification Integration Strategy

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