Blockade of β-adrenergic signaling suppresses inflammasome and alleviates cardiac fibrosis

Dang, Song; Zhang, Zhen-Ye; Li, Ku-lin; Zheng, Jie; Qian, Lingling; Liu, Xiaoyu; Wang, Ying; Changying, Zhang; Zhao, Xiaoxi; Yu, Zhi‐Ming; Wang, Ruxing; Jiang, Tingbo

doi:10.21037/atm.2020.02.31

Cited by 19 publications

(13 citation statements)

References 26 publications

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“…While radioligand binding assays are a more direct measure of receptor functionality, gene expression has been shown to correlate with binding and downstream β‐AR signaling. 36 , 37 , 38 At baseline, sex differences in expression of ADRB1 and ADRB2 were observed, with male CFs expressing higher levels of both ADRB1 and ADRB2 compared with female CFs (Figure 6A ). This result suggested to us that males may be more responsive to ISO treatment than females, and we found that after 3 days of ISO treatment, male CFs expressed significantly more ADRB1 and ADRB2 than female CFs (Figure 6B ).…”

Section: Resultsmentioning

confidence: 99%

Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to β‐Adrenergic Stimulation

Peter

Walker

Ceccato

et al. 2021

JAHA

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Background Biological sex is an important modifier of cardiovascular disease and women generally have better outcomes compared with men. However, the contribution of cardiac fibroblasts (CFs) to this sexual dimorphism is relatively unexplored. Methods and Results Isoproterenol (ISO) was administered to rats as a model for chronic β‐adrenergic receptor (β‐AR)‐mediated cardiovascular disease. ISO‐treated males had higher mortality than females and also developed fibrosis whereas females did not. Gonadectomy did not abrogate this sex difference. To determine the cellular contribution to this phenotype, CFs were studied. CFs from both sexes had increased proliferation in vivo in response to ISO, but CFs from female hearts proliferated more than male cells. In addition, male CFs were significantly more activated to myofibroblasts by ISO. To investigate potential regulatory mechanisms for the sexually dimorphic fibrotic response, β‐AR mRNA and PKA (protein kinase A) activity were measured. In response to ISO treatment, male CFs increased expression of β1‐ and β2‐ARs, whereas expression of both receptors decreased in female CFs. Moreover, ISO‐treated male CFs had higher PKA activity relative to vehicle controls, whereas ISO did not activate PKA in female CFs. Conclusions Chronic in vivo β‐AR stimulation causes fibrosis in male but not female rat hearts. Male CFs are more activated than female CFs, consistent with elevated fibrosis in male rat hearts and may be caused by higher β‐AR expression and PKA activation in male CFs. Taken together, our data suggest that CFs play a substantial role in mediating sex differences observed after cardiac injury.

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Section: Resultsmentioning

confidence: 99%

Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to β‐Adrenergic Stimulation

Peter

Walker

Ceccato

et al. 2021

JAHA

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“…The NLRP3 inhibitor MCC950 suppressed myocardial infarctioninduced NLRP3 inflammasome activation, alleviated cardiac inflammation and fibrosis, and improved cardiac function (Gao et al, 2019). Chronic β-adrenergic receptor (AR) activation in a pressure overload model and direct acute activation of β-AR led to cardiac fibrosis in an NLRP3 inflammasomedependent manner (Xiao et al, 2018;Dang et al, 2020). Pressure overload caused activation of the NLRP3 inflammasome via calcium/calmodulin dependent protein kinase (CaMK)IIδ, resulting in cardiac fibrosis and dysfunction (Suetomi et al, 2018).…”

Section: The Pathological Effect Of Inflammasome Activation In Heart Failurementioning

confidence: 99%

The Role of the Inflammasome in Heart Failure

Dong

Zhang

et al. 2021

Front. Physiol.

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Inflammation promotes the development of heart failure (HF). The inflammasome is a multimeric protein complex that plays an essential role in the innate immune response by triggering the cleavage and activation of the proinflammatory cytokines interleukins (IL)-1β and IL-18. Blocking IL-1β with the monoclonal antibody canakinumab reduced hospitalizations and mortality in HF patients, suggesting that the inflammasome is involved in HF pathogenesis. The inflammasome is activated under various pathologic conditions that contribute to the progression of HF, including pressure overload, acute or chronic overactivation of the sympathetic system, myocardial infarction, and diabetic cardiomyopathy. Inflammasome activation is responsible for cardiac hypertrophy, fibrosis, and pyroptosis. Besides inflammatory cells, the inflammasome in other cardiac cells initiates local inflammation through intercellular communication. Some inflammasome inhibitors are currently being investigated in clinical trials in patients with HF. The current evidence suggests that the inflammasome is a critical mediator of cardiac inflammation during HF and a promising therapeutic target. The present review summarizes the recent advances in both basic and clinical research on the role of the inflammasome in HF.

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“…On the other hand, there has been clear evidence that long-term beta-adrenergic stimulation promotes cardiac remodeling, including hypertrophy, fibrosis and the downregulation of several ion channels via transcriptional and post-translational modifications, potentially creating a substrate for cardiac arrhythmias (22,37,38).…”

Section: Beta-adrenergic Activation Reduces the Apd And Lowers The Cellular Proarrhythmic Risk Of Chloroquine And Azithromycinmentioning

confidence: 99%

Beta-Adrenergic Receptor Stimulation Limits the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

Sutanto¹,

Heijman²

2020

Preprint

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Background: The antimalarial drug chloroquine and antimicrobial drug azithromycin have received significant attention during the current COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection), and may influence the electrophysiological effects of chloroquine and azithromycin. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of chloroquine and azithromycin using a detailed in silico model of ventricular electrophysiology. Methods: Concentration-dependent chloroquine and azithromycin-induced alterations in ion-channel function were incorporated into the Heijman canine ventricular cardiomyocyte model. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 592 models accommodating inter-individual variability. Sympathetic stimulation was simulated by an increase in pacing rate and experimentally validated isoproterenol-induced changes in ion-channel function. Results: At 1 Hz pacing, therapeutic doses of chloroquine and azithromycin (5 and 20 µM, respectively) individually prolonged AP duration (APD) by 33% and 13%. Their combination produced synergistic APD prolongation (+161%) with incidence of proarrhythmic early afterdepolarizations in 53.5% of models. Increasing the pacing frequency to 2 Hz shortened APD and together with 1 µM isoproterenol corrected the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of 0.1-1 µM isoproterenol. Conclusion: Sympathetic stimulation limits chloroquine- and azithromycin-induced proarrhythmia by reducing their APD-prolonging effect, suggesting the importance of heart rate and autonomic status monitoring in particular conditions (e.g., COVID-19).

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Blockade of β-adrenergic signaling suppresses inflammasome and alleviates cardiac fibrosis

Cited by 19 publications

References 26 publications

Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to β‐Adrenergic Stimulation

Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to β‐Adrenergic Stimulation

The Role of the Inflammasome in Heart Failure

Beta-Adrenergic Receptor Stimulation Limits the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

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