Department of Medicine, Division of Infectious Diseases and Immunology
Cellular and Molecular Physiology | Immunology and Infectious Disease | Infectious Disease
Background: Obesity is an increasingly prevalent metabolic disorder in the modern world and is associated with structural and functional changes in the heart. The NLRP3 inflammasome is an innate immune sensor that can be activated in response to endogenous danger signals and triggers activation of interleukin (IL)-1beta and IL-18. Increasing evidence points to the involvement of the NLRP3 inflammasome in obesity-induced inflammation and insulin resistance, and we hypothesized that it also could play a role in the development of obesity induced cardiac alterations.
Methods and Results: WT, Nlrp3 (-/-), and ASC (-/-) (Pycard (-/-)) male mice were exposed to high fat diet (HFD; 60 cal% fat) or control diet for 52 weeks. Cardiac structure and function were evaluated by echocardiography and magnetic resonance imaging, respectively. Whereas, NLRP3 and ASC deficiency did not affect the cardiac hypertrophic response to obesity, it was preventive against left ventricle concentric remodeling and impairment of diastolic function. Furthermore, whereas NLRP3 and ASC deficiency attenuated systemic inflammation in HFD fed mice; long-term HFD did not induce significant cardiac fibrosis or inflammation, suggesting that the beneficial effects of NLRP3 inflammasome deficiency on myocardial remodeling at least partly reflect systemic mechanisms. Nlrp3 and ASC (Pycard) deficient mice were also protected against obesity-induced systemic metabolic dysregulation, as well as lipid accumulation and impaired insulin signaling in hepatic and cardiac tissues.
Conclusions: Our data indicate that the NLRP3 inflammasome modulates cardiac concentric remodeling in obesity through effects on systemic inflammation and metabolic disturbances, with effect on insulin signaling as a potential mediator within the myocardium.
NLRP3, cardiac remodeling, heart, high-fat diet, inflammasome, obesity
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Copyright © 2019 Sokolova, Sjaastad, Louwe, Alfsnes, Aronsen, Zhang, Haugstad, Bendiksen, Øgaard, Bliksøen, Lien, Berge, Aukrust, Ranheim and Yndestad. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
Sokolova M, Sjaastad I, Louwe MC, Alfsnes K, Aronsen JM, Zhang L, Haugstad SB, Bendiksen BA, Øgaard J, Bliksøen M, Lien E, Berge RK, Aukrust P, Ranheim T, Yndestad A. NLRP3 Inflammasome Promotes Myocardial Remodeling During Diet-Induced Obesity. Front Immunol. 2019 Jul 16;10:1621. doi: 10.3389/fimmu.2019.01621. PMID: 31379826; PMCID: PMC6648799. Link to article on publisher's site
Frontiers in immunology
Sokolova M, Lien E, Sjaastad I, Louwe MC, Alfsnes K, Aronsen JM, Zhang L, Haugstad SB, Bendiksen BA, Ogaard J, Bliksoen M, Berge RK, Aukrust P, Ranheim T, Yndestad A. (2019). NLRP3 Inflammasome Promotes Myocardial Remodeling During Diet-Induced Obesity. Infectious Diseases and Immunology Publications. https://doi.org/10.3389/fimmu.2019.01621. Retrieved from https://escholarship.umassmed.edu/infdis_pp/413
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