Gasdermin D Mediates Inflammation-Induced Defects in Reverse Cholesterol Transport and Promotes Atherosclerosis
| العنوان: | Gasdermin D Mediates Inflammation-Induced Defects in Reverse Cholesterol Transport and Promotes Atherosclerosis |
|---|---|
| المؤلفون: | Emmanuel Opoku, Cynthia Alicia Traughber, David Zhang, Amanda J. Iacano, Mariam Khan, Juying Han, Jonathan D. Smith, Kailash Gulshan |
| المصدر: | Frontiers in Cell and Developmental Biology, Vol 9 (2021) Frontiers in Cell and Developmental Biology |
| بيانات النشر: | Frontiers Media S.A., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, medicine.medical_specialty, QH301-705.5, ABCA1, Inflammation, 030204 cardiovascular system & hematology, Lesion, Cell and Developmental Biology, 03 medical and health sciences, chemistry.chemical_compound, AIM2, 0302 clinical medicine, PIP2, Internal medicine, medicine, Biology (General), Original Research, Foam cell, biology, Cholesterol, gasdermin D, Reverse cholesterol transport, cholesterol, Inflammasome, Cell Biology, 030104 developmental biology, Endocrinology, chemistry, inflammation, IL-1β, LDL receptor, biology.protein, medicine.symptom, atherosclerosis, Developmental Biology, medicine.drug |
| الوصف: | 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 in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release ~80% less IL-1β vs WT mice. The GsdmD-/- 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-/- 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 anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed the role of GsdmD in promoting atherosclerosis. The GsdmD-/- 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.SummaryGsdmD mediates inflammation-induced defects in RCT and promotes atherosclerosis. |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::faf130ad67dba7c2aed8e46cacf8bf75Test https://www.frontiersin.org/articles/10.3389/fcell.2021.715211/fullTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....faf130ad67dba7c2aed8e46cacf8bf75 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |