The NLRP3-inflammasome inhibitor MCC950 improves cardiac function in a HFpEF mouse model

Heart failure with preserved ejection fraction (HFpEF) is posing a significant medical challenge due to its growing prevalence, high hospitalization rates and limited response to current treatment options. Accumulating evidence suggests that a comorbidity-driven systemic pro-inflammatory state, incl...

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Bibliographic Details
Published in:Biomedicine & pharmacotherapy 2024-12, Vol.181, p.117711, Article 117711
Main Authors: Li, Sunhuo, Withaar, Coenraad, Rodrigues, Patricia G., Zijlstra, Sietske N., de Boer, Rudolf A., Silljé, Herman H.W., Meems, Laura M.G.
Format: Article
Language:English
Subjects:
Angiotensin II
Animals
Diastolic function
Diet, High-Fat - adverse effects
Disease Models, Animal
Female
Fibrosis
Furans - pharmacology
Heart Failure - drug therapy
Heart Failure - physiopathology
Heterocyclic Compounds, 4 or More Rings - pharmacology
HFpEF
Indenes - pharmacology
Inflammasome
Inflammasomes - antagonists & inhibitors
Inflammasomes - drug effects
Inflammasomes - metabolism
Mice
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
NLRP3
Obesity
Stroke Volume - drug effects
Sulfonamides - pharmacology
Sulfones - pharmacology
Ventricular Function, Left - drug effects
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Summary:Heart failure with preserved ejection fraction (HFpEF) is posing a significant medical challenge due to its growing prevalence, high hospitalization rates and limited response to current treatment options. Accumulating evidence suggests that a comorbidity-driven systemic pro-inflammatory state, including activation of the NLRP3 inflammasome, contributes to the pathogenesis of HFpEF. This study aimed to investigate the potential cardiac protective effects of the selective NLRP3 inhibitor MCC950, in a mouse model of HFpEF. HFpEF was obtained in 18–22 months old female mice using high-fat diet (HFD) and angiotensin II (AngII) infusion. Mice developed HFpEF and comorbidities such as obesity, type 2 diabetes, and hypertension. MCC950 was added to HFD and groups were treated for four weeks until the study endpoint. MCC950 treatment resulted in lower plasma IL-18 levels (-47.3 %), illustrating target engagement. First, we observed that MCC950 treatment improved left ventricular function, demonstrated by enhanced global longitudinal strain (GLS, 3.9 %, P
ISSN:0753-3322
1950-6007
1950-6007
DOI:10.1016/j.biopha.2024.117711