1. Tanshinone IIA attenuates atherosclerosis via inhibiting NLRP3 inflammasome activation.
- Author
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Wen J, Chang Y, Huo S, Li W, Huang H, Gao Y, Lin H, Zhang J, Zhang Y, Zuo Y, Cao X, and Zhong F
- Subjects
- Animals, Aorta metabolism, Aorta pathology, Atherosclerosis pathology, CD36 Antigens drug effects, CD36 Antigens metabolism, Diet, High-Fat, Inflammasomes metabolism, Lipoproteins, LDL drug effects, Lipoproteins, LDL metabolism, Macrophages metabolism, Mice, Mice, Knockout, ApoE, NF-kappa B drug effects, NF-kappa B metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Scavenger Receptors, Class E drug effects, Scavenger Receptors, Class E metabolism, Abietanes pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Aorta drug effects, Atherosclerosis metabolism, Inflammasomes drug effects, Macrophages drug effects, NLR Family, Pyrin Domain-Containing 3 Protein drug effects
- Abstract
Tanshinone IIA (Tan IIA) possesses potent anti-atherogenic function, however, the underlying pharmacological mechanism remains incompletely understood. Previous studies suggest that oxidized LDL (oxLDL)-induced NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome activation in macrophages plays a vital role in atherogenesis. Whether the anti-atherogenic effect of Tan IIA relies on the inhibition of the NLRP3 inflammasome has not been investigated before. In this study, we found that Tan IIA treatment of high-fat diet fed ApoE-/- mice significantly attenuated NLRP3 inflammasome activation in vivo. Consistently, Tan IIA also potently inhibited oxLDL-induced NLRP3 inflammasome activation in mouse macrophages. Mechanically, Tan IIA inhibited NF-κB activation to downregulate pro-interleukin (IL) -1β and NLRP3 expression, and decreased oxLDL-induced expression of lectin-like oxidized LDL receptor-1 (LOX-1) and cluster of differentiation 36 (CD36), thereby attenuating oxLDL cellular uptake and subsequent induction of mitochondrial and lysosomal damage - events that promote the NLRP3 inflammasome assembly. Through regulating both the inflammasome 'priming' and 'activation' steps, Tan IIA potently inhibited oxLDL-induced NLRP3 inflammasome activation, thereby ameliorating atherogenesis.
- Published
- 2020
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