BTK Promotes Atherosclerosis by Regulating Oxidative Stress, Mitochondrial Injury, and ER Stress of Macrophages.

Junxiong Qiu,Diefei Liang,Zhiteng Chen,Lisui Zhang,Zhuzhi Wen,Yuan Fu,Ling Li,Shi Liang,Yajing Wang,Feng Wei,Yun-Dai Chen

doi:10.1155/2021/9972413

Abstract

Atherosclerosis (AS) is a chronic metabolic disease in arterial walls, characterized by lipid deposition and persistent aseptic inflammation. AS is regarded as the basis of a variety of cardiovascular and cerebrovascular diseases. It is widely acknowledged that macrophages would become foam cells after internalizing lipoprotein particles, which is an initial factor in atherogenesis. Here, we showed the influences of Bruton's tyrosine kinase (BTK) in macrophage-mediated AS and how BTK regulates the inflammatory responses of macrophages in AS. Our bioinformatic results suggested that BTK was a potential hub gene, which is closely related to oxidative stress, ER stress, and inflammation in macrophage-induced AS. Moreover, we found that BTK knockdown could restrain ox-LDL-induced NK-κB signaling activation in macrophages and repressed M1 polarization. The mechanistic studies revealed that oxidative stress, mitochondrial injury, and ER stress in macrophages were also suppressed by BTK knockdown. Furthermore, we found that sh-BTK adenovirus injection could alleviate the severity of AS in ApoE−/− mice induced by a high-fat diet in vivo. Our study suggested that BTK promoted ox-LDL-induced ER stress, oxidative stress, and inflammatory responses in macrophages, and it may be a potential therapeutic target in AS.

Highlights

AS, which underlies myocardial infarction, vascular occlusive disease, and stroke, is a chronic metabolic disease in arterial walls, characterized by lipid deposition and persistent aseptic inflammation [1]
We found that the number of reactive oxygen species (ROS)-positive macrophages significantly increased after Oxidative low-density lipoprotein (ox-LDL) treatment for 24 h (Figures 1(a) and 1(b))
The activation of these 3 unfolded protein response (UPR) activator proteins indicated that ox-LDL triggered ER stress in macrophages

Summary

Introduction

AS, which underlies myocardial infarction, vascular occlusive disease, and stroke, is a chronic metabolic disease in arterial walls, characterized by lipid deposition and persistent aseptic inflammation [1]. Oxidative low-density lipoprotein (ox-LDL) is contributing to atherogenesis, foam cell formation, and AS progression [6]. M1 macrophages, with the low ability to clear cholesterol and high susceptibility to become foam cells, are involved in the initial progression of AS by producing a variety of proinflammatory factors, as well as associated with endoplasmic reticulum stress (ER stress) and mitochondrial stress [7,8,9]. Accumulating evidence revealed that BTK inhibition could make sense on tumor metastasis and infection by regulating macrophage polarization, phagocytosis, and proinflammatory factor secretion, which suggested a viable therapeutic opportunity in inflammatory diseases, such as AS [20,21,22,23]. We elucidated that the severity of AS in ApoE-/- mice induced by a high-fat diet was alleviated by the sh-BTK adenovirus injection, suggesting that BTK may represent a potential therapeutic target to combat AS

Materials and Methods

Results

Discussion