Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca<sup>2+</sup> uptake and suppress cardiac arrhythmogenesis

Sander, Paulina; Feng, Michael Sheng-Fu; Schweitzer, Maria K.; Wilting, Fabiola; Gutenthaler, Sophie M.; Arduíno, Daniela M.; Fischbach, Sandra; Dreizehnter, Lisa; Moretti, Alessandra; Gudermann, Thomas; Perocchi, Fabiana; Schredelseker, Johann

doi:10.1111/bph.15630

Cited by 19 publications

(8 citation statements)

References 57 publications

(134 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…29 Among these GSDMD inhibitors, DSF is the only Food and Drug Administration–approved drug that exerts a pyroptosis inhibitory effect by blocking GSDMD pore formation. 21 DSF has also been reported to be involved in the regulation of atherosclerosis, 30 cardiac arrhythmogenesis, 31 and body weight. 32 GI-Y1 is a small molecule GSDMD inhibitor developed by our research group, which inhibits the binding of gasdermin D N-terminal domain to cell membrane.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis

Fan,

Han,

Zhong

et al. 2024

ATVB

View full text Add to dashboard Cite

BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE −/− and Gsdmd −/− ApoE −/− mice, bone marrow transplantation, and AAV-F4/80-shGSDMD were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd −/− attenuates the atherosclerotic lesion area in high-fat diet–fed ApoE −/− mice. We performed single-cell RNA sequencing of ApoE −/− and Gsdmd −/− ApoE −/− mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis

Fan,

Han,

Zhong

et al. 2024

ATVB

View full text Add to dashboard Cite

show abstract

“…These MiCUps were tested both in mice and RYR2 (p. (Ser406Leu)) patient iPSC-CMs and were able to reduce episodes of stress-induced ventricular tachycardia in mice and reduce arrhythmogenic Ca 2+ waves in iPSC-CMs [87]. Two other MiCUps, ezetimibe and disulfiram, suppressed arrhythmogenesis in patient iPSC-CMs [88] (genetic variant not specified). Another way to modulate calcium is by inhibiting the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) with a CaMKII inhibitory peptide, which is successful in reducing the abnormal Ca 2+ release events and frequency of Ca 2+ sparks in two CPVT RYR2 (p.(Ser404Arg)/p.…”

Section: Drug Testingmentioning

confidence: 99%

iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development

2023

View full text Add to dashboard Cite

With the discovery of induced pluripotent stem cell (iPSCs) a wide range of cell types, including iPSC-derived cardiomyocytes (iPSC-CM), can now be generated from an unlimited source of somatic cells. These iPSC-CM are used for different purposes such as disease modelling, drug discovery, cardiotoxicity testing and personalised medicine. The 2D iPSC-CM models have shown promising results, but they are known to be more immature compared to in vivo adult cardiomyocytes. Novel approaches to create 3D models with the possible addition of other (cardiac) cell types are being developed. This will not only improve the maturity of the cells, but also leads to more physiologically relevant models that more closely resemble the human heart. In this review, we focus on the progress in the modelling of inherited cardiac arrhythmias in both 2D and 3D and on the use of these models in therapy development and drug testing.

show abstract

“…Ezetimibe and disulfiram have been recently identified as MiCUps, proving to efficiently suppress arrhythmogenesis in different experimental models. The identification of such compounds underscores mitochondrial Ca 2+ uptake as a pharmacological target [ 213 ].…”

Section: Therapeutic Approaches Targeting Mamsmentioning

confidence: 99%

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

et al. 2022

View full text Add to dashboard Cite

Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

show abstract

Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca²⁺ uptake and suppress cardiac arrhythmogenesis

Abstract: Ethics approval statementAll human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Cited by 19 publications

References 57 publications

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis

iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Contact Info

Product

Resources

About

Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca2+ uptake and suppress cardiac arrhythmogenesis

Abstract: Ethics approval statementAll human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Cited by 19 publications

References 57 publications

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis

iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Contact Info

Product

Resources

About

Approved drugs ezetimibe and disulfiram enhance mitochondrial Ca²⁺ uptake and suppress cardiac arrhythmogenesis