Loss of MD1 exacerbates myocardial ischemia/reperfusion injury and susceptibility to ventricular arrhythmia

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

doi:10.1016/j.ejphar.2018.11.025

Cited by 32 publications

(36 citation statements)

References 36 publications

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“…Among these candidate signaling pathways, the toll-like receptor (TLR) signaling pathway was identified as the relatively most significantly pathway. Previous studies reported that TLR4/NF-κB signaling cascades contributes to VA under myocardial ischemia condition ( Jiang et al., 2019 ; Wang et al., 2019 ). Our former work demonstrated that TLR4/MyD88/CaMKII signaling pathway contributed to obesity-induced ventricular electrical remodeling ( Shuai et al., 2019 ).…”

Section: Discussionmentioning

confidence: 96%

Shensong Yangxin Protects Against Metabolic Syndrome-Induced Ventricular Arrhythmias by Inhibiting Electrical Remodeling

et al. 2020

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Shensong Yangxin (SSYX) is a traditional Chinese medicine, which has been proven to improve the clinical symptoms of arrhythmia. However, the role of SSYX in metabolic syndrome (MetS)-induced electrical remodeling remains to be fully elucidated. Here, we sought to clarify whether SSYX can alter the electrophysiological remodeling of cardiac myocytes from MetS rats by regulating transient outward potassium current ( I to ) and calcium current ( I Ca-L ). Male Wistar rats were subjected to 16 weeks of high-carbohydrate, high-fat to produce a MetS model group. SSYX (0.4 g/kg) was administrated by daily gavage 8 weeks following high-carbohydrate, high-fat for 8 weeks. In vivo electrophysiological study was performed to evaluated ventricular arrhythmias (VA) vulnerability and electrophysiological properties. The potential electrical mechanisms were estimated by whole-cell patch-clamp and molecular analysis. The H9C2 cells were used to verify the protective role of SSYX in vitro . After 16-week high-carbohydrate, high-fat feeding, MetS model rats showed increased body weight (BW), blood pressure (BP), blood sugar (BS), heart rate (HR) and heart weights to tibia length (HW/TL) ratio. Furthermore, MetS rats depicted increased VA inducibility, shortened effective refractory period (ERP) and prolonged action potential duration (APD). Lower I Ca-L and I to current densities were observed in MetS rats than CTL rats. Additionally, MetS rats exhibited significantly increased cardiac fibrosis, decreased Cx43 expression and protein levels of Cav1.2, Kv4.2, Kv4.3 than CTL group. As expected, these MetS-induced effects above were reversed when SSYX was administrated. Mechanistically, SSYX administrated significantly down-regulated the TLR4/MyD88/CaMKII signaling pathway both in vivo and in vitro . Collectively, our data indicated that the electrical remodeling induced by MetS contributed to the increased VA susceptibility. SSYX protects against MetS-induced VA by inhibiting electrical remodeling through TLR4/MyD88/CaMKII signaling pathway.

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Section: Discussionmentioning

confidence: 96%

Shensong Yangxin Protects Against Metabolic Syndrome-Induced Ventricular Arrhythmias by Inhibiting Electrical Remodeling

et al. 2020

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“…The TLR4-mediated signal transduction pathway plays an essential role in cardiac structural and electrical remodeling caused by obesity [ 13 , 14 ]. Our previous studies illuminated that loss of MD1, a negative physiological regulator of the TLR4 signaling pathway, could worsen cardiac structural and electrical remodeling in a pathological condition, such as hypertrophic cardiomyopathy and ischemia/reperfusion injury [ 6 , 8 ]. Our current study found that MD1 is downregulated in the hearts of obese mice [ 9 , 11 ], and loss of MD1 markedly prolonged APD and increased susceptibility to VA via enhanced activation of the TLR4/MyD88/CaMKII signaling pathway in HFD-fed mice [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…The MD1-RP105 complex can directly interact with the myeloid differentiation protein 2 (MD2)-Toll-like receptor 4 (TLR4) complex by a lateral binding, acting as a negative physiological regulator of the TLR4 signaling pathway [5]. Our previous studies found that MD1 expression was downregulated in heart failure patients [6,7], and loss of MD1 could worsen structural and electrical remodeling under pressure overload and ischemia/reperfusion injury conditions via increased the activation of the TLR4 signaling pathway [6,8]. Interestingly, we also found that MD1 deletion had no significant effect on the cardiac structure in wild-type (WT) mice under physiological conditions [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Our previous studies found that MD1 expression was downregulated in heart failure patients [6,7], and loss of MD1 could worsen structural and electrical remodeling under pressure overload and ischemia/reperfusion injury conditions via increased the activation of the TLR4 signaling pathway [6,8]. Interestingly, we also found that MD1 deletion had no significant effect on the cardiac structure in wild-type (WT) mice under physiological conditions [6][7][8][9][10][11]. Moreover, downregulated MD1 does not activate the TLR4 signaling pathway in both in vitro and in vivo experiments [7,9].…”

Section: Introductionmentioning

confidence: 99%

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The effect of MD1 on potassium and L-type calcium current of cardiomyocytes from high-fat diet mice

Shuai

Kong

et al. 2020

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Myeloid differentiation protein 1 (MD1) is exerted an anti-arrhythmic effect in obese mice. Therefore, we sought to clarify whether MD1 can alter the electrophysiological remodeling of cardiac myocytes from obese mice by regulating voltage-gated potassium current and calcium current. MD1 knockout (KO) and wild type (WT) mice were given a high-fat diet (HFD) for 20 weeks, starting at the age of 6 weeks. The potential electrophysiological mechanisms were estimated by whole-cell patch-clamp and molecular analysis. After 20-week HFD feeding, action potential duration (APD) from left ventricular myocytes of MD1-KO mice revealed APD 20 , APD 50 , and APD 90 were profoundly enlarged. Furthermore, HFD mice showed a decrease in the fast transient outward potassium currents (I to,f), slowly inactivating potassium current (I K, slow), and inward rectifier potassium current (I K1). Besides, HFD-fed mice showed that the current density of I CaL was significantly lower, and the haft inactivation voltage was markedly shifted right. These HFD induced above adverse effects were further exacerbated in KO mice. The mRNA expression of potassium ion channels (Kv4.2, Kv4.3, Kv2.1, Kv1.5, and Kir2.1) and calcium ion channel (Cav1.2) was markedly decreased in MD1-KO HFD-fed mice. MD1 deletion led to down-regulated potassium currents and slowed inactivation of L-type calcium channel in an obese mice model.

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“…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). However, the relationship between MD1 and activation of NLRP3 inflammasome‐mediated cardiac sympathetic hyperactivity in HFpEF‐induced VA has not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

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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Loss of MD1 exacerbates myocardial ischemia/reperfusion injury and susceptibility to ventricular arrhythmia

Cited by 32 publications

References 36 publications

Shensong Yangxin Protects Against Metabolic Syndrome-Induced Ventricular Arrhythmias by Inhibiting Electrical Remodeling

Shensong Yangxin Protects Against Metabolic Syndrome-Induced Ventricular Arrhythmias by Inhibiting Electrical Remodeling

The effect of MD1 on potassium and L-type calcium current of cardiomyocytes from high-fat diet mice

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

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