Toll-like receptor 4 activation promotes cardiac arrhythmias by decreasing the transient outward potassium current (Ito) through an IRF3-dependent and MyD88-independent pathway

Monnerat, Gustavo; Alonso, Hiart; Gallego, Mónica; Alarcón, Micaela López; Bassani, Rosana A.; Casis, Óscar; Medei, Emiliano

doi:10.1016/j.yjmcc.2014.08.012

Cited by 43 publications

(40 citation statements)

References 34 publications

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“…Rest does not typically affect the SR Ca 2+ load, unless Ca 2+ efflux by the Na + /Ca 2+ exchanger (NCX) is enhanced2526. In this case, however, one would expect a greater ratio of the rate constants of [Ca 2+ ]i re-uptake upon application of 10 mM caffeine or by electrical stimulation27, in which Ca 2+ clearance from the cytosol is dependent mainly on the NCX and the SR Ca 2+ ATPase plus NCX, respectively28. However, neither the rate constants of Ca 2+ re-uptake/efflux (not shown), nor their ratio (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice

et al. 2016

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Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1β in DM mice. IL-1β causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1β-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1β axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1β as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.

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Section: Resultsmentioning

confidence: 99%

“…The following parameters were analysed: resting membrane potential, action potential amplitude and APD at 90% (APD 90 ) repolarization. For specific set of experiments left ventricular muscle strips, from Wistar rats were incubated for 24 h at 4 °C with Tyrode's solution containing agonist or not as previously described68.…”

Section: Methodsmentioning

confidence: 99%

Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice

et al. 2016

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“…This is closely attributed to myocardial infarction and ventricular remodeling. 17,27) However, there is a lack of data on TLR2 and TLR4 expression in acute myocardial infarction patients with or without new-onset atrial fibrillation.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptors 2 and 4 Predict New-Onset Atrial Fibrillation in Acute Myocardial Infarction Patients

Zhang

Shao

2018

Int. Heart J.

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SummaryMyocardial infarction (MI) can cause new-onset atrial fibrillation (AF) due to cardiac remodeling. As a recent study has shown, inflammatory factors are closely tied to cell death and survival in myocardial ischemia injury. Toll-like receptors (TLRs) have been shown to participate in the process of myocardial infarction as innate immune factors.The subjects were divided into 3 groups: healthy controls (n = 82), MI patients (n = 84), and AFMI (newonset atrial fibrillation after myocardial infarction) patients (n = 85). Peripheral blood mononuclear cell (PBMC) TLR mRNA expression was detected by rt-PCR. Western blot was used to analyze PBMC TLRs and their downstream signal protein expression. PBMCs were presented as TLR2 expression or TLR4 expression using flow cytometry.From mRNA to protein detection, PBMC TLR2 and TLR4 were significantly higher in the AFMI group than in the control group and MI group. A similar tendency was also observed in the expression of downstream signaling proteins. When further analyzed with TLR2 and TLR4 antibodies by flow cytometry, PBMC levels also appeared to be higher in AFMI patients than those in MI patients and the healthy control group.In our study, PBMC TLRs and their downstream signaling proteins were significantly higher in the acute myocardial infarction patients with new-onset atrial fibrillation compared with healthy people and acute myocardial infarction patients without new-onset atrial fibrillation. They have the potential to be novel biomarkers for new-onset atrial fibrillation after acute myocardial infarction.(Int Heart J 2018; 59: 64-70) Key words: Innate immune A s one component of the global burden of cardiac arrhythmia disease, atrial fibrillation (AF) is generally divided into valvular and non-valvular AF. Myocardial infarction (MI) is an independent risk factor for new-onset AF which occurs in 6% to 21% of acute MI patients due to post myocardial infarction remodeling. [1][2][3][4][5] Unfortunately, AF is highly associated with substantial morbidity and mortality increases after myocardial infarction. 6-8) Editorial p.3Innate immune factors play important roles in most cardiac diseases. [9][10][11] As data has shown in recent research, toll-like receptors increase in either plasma or tissues as innate immune factors in ischemia heart diseases and arrhythmias diseases. [12][13][14] Notably, TLR4 could directly stimulate macrophages and induce atheroma formation, while TLR4 deficiency has been shown to have a protective effect against myocardial ischemic injury. 15,16) Furthermore, there is some evidence for TLR4 in ventricular remodeling after acute myocardial infarction. 17,18) However, the effect of TLR2 on heart disease remains controversial. In TLR2 knock-out mice, there was no obvious difference in infarct size compared to wild type mice, although a negative effect on fibrosis in the non-infarcted area and a positive effect on left ventricular remodeling have been reported. 19,20) However, TLR2 also has been found to trigger atrial fibrillation and fa...

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“…In addition to the well‐established role of TLR signaling in the immune system, increasing evidence suggests that TLR signaling exerts a crucial effect on the pathogenesis of multiple cardiovascular diseases 25, 26. In the vasculature, activated TLR signaling increases VSMC phenotypic switching, proliferation, and migration, which are essential processes in neointima formation 12, 13, 27.…”

Section: Discussionmentioning

confidence: 99%

Tollip Negatively Regulates Vascular Smooth Muscle Cell–Mediated Neointima Formation by Suppressing Akt‐Dependent Signaling

Huang

Gong

Cheng

et al. 2018

JAHA

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BackgroundTollip, a well‐established endogenous modulator of Toll‐like receptor signaling, is involved in cardiovascular diseases. The aim of this study was to investigate the role of Tollip in neointima formation and its associated mechanisms.Methods and ResultsIn this study, transient increases in Tollip expression were observed in platelet‐derived growth factor‐BB–treated vascular smooth muscle cells and following vascular injury in mice. We then applied loss‐of‐function and gain‐of‐function approaches to elucidate the effects of Tollip on neointima formation. While exaggerated neointima formation was observed in Tollip‐deficient murine neointima formation models, Tollip overexpression alleviated vascular injury–induced neointima formation by preventing vascular smooth muscle cell proliferation, dedifferentiation, and migration. Mechanistically, we demonstrated that Tollip overexpression may exert a protective role in the vasculature by suppressing Akt‐dependent signaling, which was further confirmed in rescue experiments using the Akt‐specific inhibitor (AKTI).ConclusionsOur findings indicate that Tollip protects against neointima formation by negatively regulating vascular smooth muscle cell proliferation, dedifferentiation, and migration in an Akt‐dependent manner. Upregulation of Tollip may be a promising strategy for treating vascular remodeling–related diseases.

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Toll-like receptor 4 activation promotes cardiac arrhythmias by decreasing the transient outward potassium current (Ito) through an IRF3-dependent and MyD88-independent pathway

Cited by 43 publications

References 34 publications

Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice

Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice

Toll-Like Receptors 2 and 4 Predict New-Onset Atrial Fibrillation in Acute Myocardial Infarction Patients

Tollip Negatively Regulates Vascular Smooth Muscle Cell–Mediated Neointima Formation by Suppressing Akt‐Dependent Signaling

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