MD1 Deficiency Promotes Inflammatory Atrial Remodelling Induced by High-Fat Diets

Shuai, Wei; Kong, Bin; Fu, Hui; Shen, Caijie; Jiang, Xiaobo; Huang, He

doi:10.1016/j.cjca.2018.11.020

Cited by 43 publications

(52 citation statements)

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“…Several studies have shown that, before the onset of AF, shorter atrial ERPs and a longer IACT are associated with higher inducibility of AF in HF patients and animals . Moreover, earlier work from our group showed that MD1 deletion can increase the AF induction rate in the setting of HFD . Therefore, a deficiency in MD1 can increase vulnerability to AF caused by aldosterone‐induced HFpEF.…”

Section: Discussionmentioning

confidence: 80%

“…The increase in proinflammatory cytokines in KO‐Aldo mice was markedly attenuated in WT‐Aldo mice ( P < 0.05) ( Figure A ). Our previous study reported that the nuclear factor kappa B (NF‐κB) signalling pathway play a vital role in regulating the inflammatory response and that MD1 has an effect on NF‐κB suppression in the setting of obesity . Therefore, the NF‐κB signalling pathway was investigated to confirm MD1 function after aldosterone infusion.…”

Section: Resultsmentioning

confidence: 99%

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Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

et al. 2020

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Aims Myeloid differentiation protein 1 (MD1) is expressed in the mammalian heart and exerts an anti-arrhythmic effect. Atrial fibrillation (AF) is closely related to heart failure with preserved ejection fraction (HFpEF). The potential impact of MD1 on AF vulnerability in an HFpEF model is not clear. Methods and results MD1 knock-out and wild-type (WT) mice were subjected to uninephrectomy and continuous saline or D-aldosterone infusion and given 1% sodium chloride drinking water for 4 weeks. Echocardiographic and haemodynamic measurements, electrophysiological studies, Masson staining, and molecular analysis were performed. Aldosterone-infused WT mice develop HFpEF with left ventricular hypertrophy, moderate hypertension, pulmonary congestion, and diastolic dysfunction. Aldosterone infusion increased the vulnerability of WT mice to AF, as shown by a prolonged interatrial conduction time, shortened effective refractory period, and higher incidence of AF. In addition, aldosterone infusion increased myocardial fibrosis and inflammation, decreased sarcoplasmic reticulum Ca 2+ -ATPase 2a protein expression and the phosphorylation of phospholamban at Thr17, and increased sodium/calcium exchanger 1 protein expression and the phosphorylation of ryanodine receptor 2 in WT mice. All of the above adverse effects of aldosterone infusion were further exacerbated in MD1 knock-out mice compare with WT mice. Mechanistically, MD1 deletion increased the activation of the toll-like receptor 4/calmodulindependent protein kinase II signalling pathway in in vivo and in vitro experiments. Conclusions MD1 deficiency increases the vulnerability of HFpEF mice to AF. This is mainly caused by aggravated maladaptive left atrial fibrosis and inflammation and worsened dysregulation of calcium handling, which is induced by the enhanced activation of the toll-like receptor 4/calmodulin-dependent protein kinase II signalling pathway.

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Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

et al. 2020

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“…Our previous studies found that MD1 ‐KO functions via activation NF‐κB signalling (Shuai et al., 2019b; Xiong et al., 2017). Recently, accumulating evidence has suggested that the NLRP3 inflammasome, composed of apoptosis‐associated speck‐like protein containing a CARD (ASC), caspase‐1 and NLRP3, has been recognized as an important mediator of the inflammatory response (Franchi, Eigenbrod, Muñoz‐Planillo, & Nuñez, 2009; Sutterwala et al., 2006).…”

Section: Discussionmentioning

confidence: 97%

“…In the present study, increased infiltration of macrophages and IL‐1β release were found in the ventricle of mice with HFpEF, which was in line with previous reports (Ter Maaten et al., 2016; Reddy et al, 2018). Previous studies demonstrated that MD1 serves as a negative inflammatory regulator and participates in several cardiac pathological processes (Shuai et al., 2019b; Xiong et al., 2017); therefore, we tested whether MD1 ‐KO enhanced the HFpEF‐induced inflammatory response. Our results showed that MD1 ‐KO increased the HFpEF‐induced IL‐1β release.…”

Section: Discussionmentioning

confidence: 99%

“…Myeloid differentiation 1 (MD1) serves as a negative regulator of the Toll‐like receptor 4 (TLR4) signalling pathway (Divanovic et al., 2005). Our previous studies demonstrated that MD1 serves as a negative inflammatory regulator and participates in several cardiac pathological processes via activation NF‐κB signalling (Shuai et al., 2019b; Xiong et al., 2017), and activation of the NLRP3 inflammasome required NF‐κB signalling. Moreover, our former studies demonstrated that MD1 deficiency facilitates VA by deteriorating electrical remodelling, which manifested as prolongation of action potential duration (APD) and a lower threshold for APD alternans (Jiang et al., 2019; Shuai, Kong, Fu, Shen, & Huang, 2019a).…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Kong

Shuai

et al. 2020

Experimental Physiology

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Sympathetic hyperactivity can promote malignant ventricular arrhythmia (VA), and myeloid differentiation 1 (MD1) has been reported to play an important role in obesity-induced VA.However, it is not known whether an interaction of MD1 with sympathetic hyperactivity contributes to the VA induced by heart failure with preserved ejection fraction (HFpEF). The aim of this study was to investigate the potential interaction between MD1 and sympathetic hyperactivity in HFpEF-induced VA and the underlying mechanism. Eight-week-old MD1knockout (MD1-KO) and wild-type (WT) mice were subjected to a model of HFpEF induced by uninephrectomy, a continuous saline or d-aldosterone infusion and provision of drinking water containing 1.0% sodium chloride for 4 weeks. Echocardiography and haemodynamics were used to verify the model of HFpEF. An isolated electrophysiological study was performed to assess the susceptibility to VA. Four weeks later, the mice with HFpEF showed an increased heart weight to tibia length ratio, decreased left ventricular minimum rates of pressure rise (dP/dt min ), increased , lung weight to tibia length ratio and preserved left ventricular ejection fraction compared with WT mice. The mice with HFpEF exhibited increased susceptibility to VA, as shown by the shortened effective refractory period, prolonged action potential duration (APD), increased APD alternans threshold and higher incidence of VA. Moreover, we also found that mice with HFpEF showed impaired heart rate variability, sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin-1 release. These changes induced by HFpEF were exacerbated by MD1 deficiency. We conclude that MD1-KO contributes to sympathetic hyperactivity and facilitates VA in HFpEF via activation of the NLRP3 inflammasome. Treatment targeting MD1 and NLRP3 might decrease the risk of HFpEF-induced VA. K E Y W O R D Sheart failure with preserved ejection fraction, inflammation, sympathetic nerve 1 966wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:966-978.

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Dapagliflozin reduces pulmonary vascular damage and susceptibility to atrial fibrillation in right heart disease

et al. 2022

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Aims Sodium‐glucose cotransporter 2 inhibitors (SGLT2is) have made considerable progress in the field of heart failure, but their application in arrhythmia remains to be in‐depth. Right heart disease (RHD) often leads to right heart dysfunction and is associated with atrial fibrillation (AF). Here, we explored the possible electrophysiologic effect of dapagliflozin (a type of SGLT2is) in the development of AF in rats with RHD. Methods and results Rats in the experimental group were intraperitoneally injected with a single dose of 60 mg/kg monocrotaline (MCT group, n = 32) on the first day of the experiment, whereas rats in the control group were injected with vehicle (CTL group, n = 32). Rats in the treatment subgroup were treated with dapagliflozin solution orally (MCT + DAPA and CTL + DAPA groups) for a total of 4 weeks, whereas rats in the rest of subgroups were given sterile drinking water. After 4 weeks, echocardiography demonstrated that MCT group rats developed obvious pulmonary arterial hypertension and right heart dysfunction. In addition, there were also obvious inflammatory infiltration, fibrosis, and muscularization in right atrial and pulmonary arteries. The P‐wave duration (17.00 ± 0.53 ms, vs. 14.43 ± 0.57 ms in CTL; 14.00 ± 0.65 ms in CTL + DAPA; 14.57 ± 0.65 ms in MCT + DAPA; P < 0.05), RR interval (171.60 ± 1.48 ms, vs. 163.10 ± 1.10 ms in CTL; 163.30 ± 1.19 ms in CTL + DAPA; 163.10 ± 1.50 ms in MCT + DAPA; P < 0.05), Tpeak‐Tend interval (65.93 ± 2.55 ms, vs. 49.55 ± 1.71 ms in CTL; 48.27 ± 3.08 ms in CTL + DAPA; P < 0.05), and corrected QT interval (200.90 ± 2.40 ms, vs. 160.00 ± 0.82 ms in CTL; 160.40 ± 1.36 ms in CTL + DAPA; 176.6 ± 1.57 ms in MCT + DAPA; P < 0.01) were significantly prolonged in the MCT group after 4 weeks, whereas P‐wave amplitude (0.07 ± 0.0011 mV, vs. 0.14 ± 0.0009 mV in CTL; 0.14 ± 0.0011 mV in CTL + DAPA; 0.08 ± 0.0047 mV in MCT + DAPA; P < 0.05) and T‐wave amplitude (0.04 ± 0.002 mV, vs. 0.13 ± 0.003 mV in CTL; 0.13 ± 0.003 mV in CTL + DAPA; P < 0.01) were decreased, and atrial 90% action potential duration (47.50 ± 0.93 ms, vs. 59.13 ± 2.1 ms in CTL; 59.75 ± 1.13 ms in CTL + DAPA; 60.63 ± 1.07 ms in MCT + DAPA; P < 0.01) and effective refractory periods (41.14 ± 0.88 ms, vs. 62.86 ± 0.99 ms in CTL; 63.14 ± 0.67 ms in CTL + DAPA; 54.86 ± 0.70 ms in MCT + DAPA; P < 0.01) were shortened. Importantly, the inducibility rate (80%, vs. 0% in CTL; 10% in CTL + DAPA; 40% in MCT + DAPA; P < 0.05) and duration of AF (30.85 ± 22.90 s, vs. 0 ± 0 s in CTL; 0.24 ± 0.76 s in CTL + DAPA; 5.08 ± 7.92 s in MCT + DAPA; P < 0.05) were significantly increased, whereas the expression levels of cardiac ion...

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MD1 Deficiency Promotes Inflammatory Atrial Remodelling Induced by High-Fat Diets

Cited by 43 publications

References 39 publications

Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

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

Dapagliflozin reduces pulmonary vascular damage and susceptibility to atrial fibrillation in right heart disease

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