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Abstract/Summary
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<jats:p>Activation of inflammasomes, such as Nlrp3 and AIM2, can exacerbate atherosclerosis in mice and humans. Gasdermin D (GsdmD) serves as a final executor of inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-1β). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1β antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/AIM2 and IL-1β nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet fully clear. Here, we used <jats:italic>in vivo</jats:italic> Nlrp3 inflammasome activation to show that the GsdmD<jats:sup>–/–</jats:sup> mice release ∼80% less IL-1β vs. Wild type (WT) mice. The GsdmD<jats:sup>–/–</jats:sup> macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ∼26% decrease vs. ∼60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1β dependent fashion. The GsdmD<jats:sup>–/–</jats:sup> mice were resistant to Nlrp3 inflammasome mediated defect in RCT, with ∼32% reduction in plasma RCT vs. ∼57% reduction in WT mice, ∼17% reduction in RCT to liver vs. 42% in WT mice, and ∼37% decrease in RCT to feces vs. ∼61% in WT mice. The LDLr antisense oligonucleotides (ASO) induced hyperlipidemic mouse model showed the role of GsdmD in promoting atherosclerosis. The GsdmD<jats:sup>–/–</jats:sup> mice exhibit ∼42% decreased atherosclerotic lesion area in females and ∼33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing sections stained positive for the cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD in atherosclerotic plaques. Our data show that GsdmD mediates inflammation-induced defects in RCT and promotes atherosclerosis.</jats:p>
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1000
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Hinweis
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DeepGreen-ID: 61ad166c64d04362a710960758416482 ; metadata provieded by: DeepGreen (https://www.oa-deepgreen.de/api/v1/), LIVIVO search scope life sciences (http://z3950.zbmed.de:6210/livivo), Crossref Unified Resource API (https://api.crossref.org/swagger-ui/index.html), to.science.api (https://frl.publisso.de/), ZDB JSON-API (beta) (https://zeitschriftendatenbank.de/api/), lobid - Dateninfrastruktur für Bibliotheken (https://lobid.org/resources/search)
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