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

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.

Immune-Associated Gene Signatures and Subtypes to Predict the Progression of Atherosclerotic Plaques Based on Machine Learning

“…The preclinical animal models have revealed the significance of GZMB in atherosclerosis ( Zeglinski and Granville, 2020 ). Moreover, BTK triggers atherosclerotic plaque formation by mediating oxidative stress, mitochondrial damage, and endoplasmic reticulum stress of macrophages ( Qiu et al, 2021 ).…”

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

“…In addition, macrophages produce different proinflammatory cytokines to maintain the inflammatory response when ER stress occurs. For example, activation of the PERK/ATF4/ CHOP signaling pathway promotes the release of TNF-α and IL-1β, and activation of IRE1α/JNK signaling pathway stimulates the release of IL-1β, IL-6, and IL-8 (Li D. et al, 2021;Song et al, 2021). However, activating the LKB1/AMPK signaling pathway robustly inhibits ER stress, reduces the production of proinflammatory cytokines, and alleviates cellular inflammatory responses (Rao et al, 2019).…”

“…Increased expression of the ER stress-associated apoptosis signaling molecule C/EBP homoiogous protein (CHOP) indicates macrophage apoptosis ( Yang et al, 2020b ). Pathologically, macrophage apoptosis instigates the formation of inflammatory necrotic core, which is not conducive to the stability of advanced atherosclerotic plaques and thus underlies plaque rupture ( Qiu et al, 2021 ).…”

Proteomic Characterization of Atherosclerotic Lesions In Situ Using Percutaneous Coronary Intervention Angioplasty Balloons—Brief Report

“…25,26 BTK (Bruton tyrosine kinase) was also identified uniquely in the STEMI group (Figure S2), though it is unclear whether this is from macrophages or B cells. 27 This kinase integrates and coordinates multiple, diverse signaling proteins and is implicated in cytokine receptor signaling. It plays an important role in immune cell function and adaptive immunity, as a component of the TLR (Toll-like receptors) pathway where it is involved in the pathways linking TLR8 and TLR9 to NF-kappa-B (nuclear factor kappa-light-chain-enhancer of activated B cells).…”