Research Paper Volume 13, Issue 1 pp 910—932
Tanshinone IIA attenuates atherosclerosis via inhibiting NLRP3 inflammasome activation
- 1 College of Veterinary Medicine and College of Animal Science and Technology, Hebei Veterinary Biotechnology Innovation Center, Hebei Agricultural University, Baoding 071001, Hebei, China
- 2 Department of Cardiology, 252 Hospital of Chinese PLA, Baoding 071000, Hebei, China
- 3 Department of Central Laboratory, First Hospital of Qinhuangdao, Qinhuangdao 066000, Hebei, China
- 4 Department of Biology, College of Basic Medicine, Hebei University, Baoding 071000, Hebei, China
Received: June 29, 2020 Accepted: August 15, 2020 Published: November 16, 2020
https://doi.org/10.18632/aging.202202How to Cite
Copyright: © 2020 Wen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
Abbreviations
Tan IIA: Tanshinone IIA; oxLDL: oxidized LDL; NLR: Nod-like receptors; NLRP3: NLR Family Pyrin Domain Containing 3; RLR: RIG-I-like receptors; LOX-1: lectin-like oxidized LDL receptor-1; CD36: cluster of differentiation 36; SR-A1: scavenger receptor A1; AS: atherosclerosis; ChC: cholesterol crystal; ASC: Apoptosis-Associated Speck-Like Protein Containing CARD; ROS: Reactive oxygen species; TG: triglyceride; LDL-Ch: low-density-lipoprotein –Ch; BMDMs: bone marrow-derived macrophages; siRNA: small interfering RNA; DCFH-DA: 2´, 7´-Dichlorofluorescein diacetate; mtROS: mitochondrial ROS; ΔΨm: mitochondrial membrane potential; Nrf2: nuclear factor-E2-related factor 2; PPARγ: peroxisome proliferator-activated receptor-γ; PMSF: phenylmethylsulfonyl fluoride; DPI: Diphenyleneiodonium; LPS: polysaccharide; SSO: sulfosuccinimidyl oleate; SFN: sulforaphane; TZDs: thiazolidinediones; ELISA: enzyme-linked immunosorbent assay.