Tanshinone IIA attenuates atherosclerosis via inhibiting NLRP3 inflammasome activation.

Jiexia Wen,Wenyan Li,Yonghong Zhang,Yumei Chang,Heling Huang,Yuzhu Zuo,Shanshan Huo,Hongyu Lin,Xuebin Cao,Fei Zhong,Jianlou Zhang,Yunhuan Gao

doi:10.18632/aging.202202

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.

Highlights

Tanshinone IIA (Tan IIA) is one of the major therapeutic components of Salvia miltiorrhiza Bunge
To confirm the anti-AS effect of Tan IIA in vivo, we tested whether the administration of Tan IIA (Figure 1A) could inhibit atherogenesis in the ApoE-/- mice fed with a high-cholesterol diet (HCD)
Tan IIA had little effect on serum total Ch (T-Ch) and HDL-Ch levels (Figure 1F, 1G), it significantly decreased the amounts of low-density-lipoprotein Ch (LDL-Ch) and TG in the sera of HCD-fed ApoE-deficient mice (Figure 1H, 1I), with the strongly reduction seen in LDL-Ch (~40%)

Summary

Introduction

Tanshinone IIA (Tan IIA) is one of the major therapeutic components of Salvia miltiorrhiza Bunge. The mechanism of anti-atherogenesis of Tan IIA remains incompletely understood. This is because the pharmacological functions of Tan IIA are not entirely clear [3], but the mechanisms of AS formation are not fully elucidated [4]. The inflammasome-mediated inflammation plays a crucial role in the pathology of some cardiovascular diseases [6,7,8]. AS, a major cardiovascular disease, is a multifactorial disorder in which sterile inflammation was shown to play a pathogenic role [9]. Recent studies revealed that the NLRP3 inflammasome activation by oxidized www.aging-us.com low density lipoprotein (oxLDL) and its derived cholesterol crystal (ChC) is a key pathogenic event that drives initiation of sterile inflammation in AS [10,11,12,13,14,15,16,17]

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Results

Conclusion