BRD4 contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake

Wang, Hui; Fu, Haiping; Zhu, Rui; Wu, Xuan; Ji, Xiuqing; Li, Xuesong; Jiang, Hong; Zhe, Liu; Tang, Xin; Sun, Shixiu; Chen, Jiajing; Wang, Xin; Li, Qingguo; Ji, Yong; Chen, Hongshan

doi:10.18632/aging.103200

Cited by 48 publications

(45 citation statements)

References 47 publications

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“…Similarly, in a model of peritonitis induced in the murine reporter strain p16 Ink4a , macrophages displayed features of senescence ( Liu et al, 2019 ). Last, LPS could induce the formation of senescent-like macrophages, characterized by lipid accumulation, SASP, and a persistent DNA damage response ( Wang et al, 2020 ). Once again, a parallel with senescence is evident as senescent glial cells exhibit excessive fat deposits, a phenotype that was termed ‘‘accumulation of lipids in senescence’’ ( Ogrodnik et al, 2019 ).…”

Section: Senescent-like Macrophages: Just Another Polarization State?mentioning

confidence: 99%

Similarities and interplay between senescent cells and macrophages

Behmoaras

Gil

2020

Journal of Cell Biology

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Senescence is a cellular program that prevents the replication of old, damaged, or cancerous cells. Senescent cells become growth arrested and undergo changes in their morphology, chromatin organization, and metabolism, and produce a bioactive secretome. This secretome, the senescence-associated secretory phenotype (SASP), mediates many of the pathophysiological effects associated with senescent cells, for example, recruiting and activating immune cells such as macrophages. The relation between senescent cells and macrophages is intriguing: senescent cells recruit macrophages, can induce them to undergo senescence, or can influence their polarization. Senescent cells and macrophages share multiple phenotypic characteristics; both have a high secretory status, increased lysosome numbers, or the ability to activate the inflammasome. Senescent cells accumulate during aging and disease, and killing them results in widespread benefits. Here we discuss similarities between senescent cells and macrophages and interpret the latest developments in macrophage biology to understand the molecular mechanisms of cellular senescence. We describe evidence and effects of senescence in macrophages and speculate on the ontogeny of the senescent-like state in macrophages. Finally, we examine the macrophage–senescent cell interplay and its impact on macrophage effector functions during inflammatory conditions and in the tumor microenvironment.

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Section: Senescent-like Macrophages: Just Another Polarization State?mentioning

confidence: 99%

Similarities and interplay between senescent cells and macrophages

Behmoaras

Gil

2020

Journal of Cell Biology

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“… 63 , 132 BRD4 may also promote the senescence and lipid accumulation in LPS-induced senescent macrophages by increasing the expression of SASP in autocrine and paracrine senescence, thereby promoting the progress of atherosclerosis. 161 Accordingly, JQ1 exhibits therapeutic effects on heart failure caused by prolonged pressure overload and a massive anterior myocardial infarction. 66 , 101 Similarly, BETi apabetalone (RVX-208) not only improves the cardiovascular outcomes of patients with type 2 diabetes after acute coronary syndrome, 162 but also decreases the risk of atherosclerotic plaque rupture and major adverse cardiac events.…”

Section: Introductionmentioning

confidence: 99%

The BET family in immunity and disease

Wang

Tang

et al. 2021

Sig Transduct Target Ther

181

146

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Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.g., TLR, NLR, and CGAS) pathways, thereby linking chromatin machinery to innate immunity under disease or pathological conditions. Mechanistically, the BET family controls the transcription of a wide range of proinflammatory and immunoregulatory genes by recognizing acetylated histones (mainly H3 and H4) and recruiting transcription factors (e.g., RELA) and transcription elongation complex (e.g., P-TEFb) to the chromatin, thereby promoting the phosphorylation of RNA polymerase II and subsequent transcription initiation and elongation. This review covers the accumulating data about the roles of the BET family in innate immunity, and discusses the attractive prospect of manipulating the BET family as a new treatment for disease.

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“…Atherosclerosis (AS) is a multifactorial disease that is closely associated with aging and involves a number of lipid metabolism disorders ( 1 ). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of cholesterol metabolism, can promote the degradation of plasma low-density lipoprotein receptor (LDLR) and increase the level of low-density lipoprotein cholesterol (LDL-C), leading to an increased risk of AS ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX‑1 in apoE<sup>‑/‑</sup> mice

Jia

Cao

et al. 2020

Exp Ther Med

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The purpose of the current study was to investigate the mechanism by which fisetin improves atherosclerosis (AS) by regulating lipid metabolism and senescence in apolipoprotein E-deficient (apoE -/- ) mice. An AS model was established by feeding apoE -/- mice a high-fat diet. Mice were randomly divided into the model group (n=18), the fisetin group (n=18) and the atorvastatin group (n=18). The control group (n=18) was composed of wild-type C57BL/6 mice of the same age and genetic background. The fisetin and atorvastatin groups were respectively treated with aqueous solutions of fisetin (12.5 mg/kg) and atorvastatin (2 mg/kg) via oral gavage daily for 12 weeks. The pathological morphology, lipid accumulation, collagen deposition of the aortic sinus were observed, serum lipids, superoxide dismutase (SOD) and malondialdehyde (MDA) levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured in the peripheral blood serum. Additionally, the expressions of proprotein convertase subtilisin/kexin type 9 (PCSK9), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), tumor suppressor protein p53 (p53), cyclin-dependent kinase inhibitor 1A (p21) and multiple tumor suppressor-1 (p16) were analyzed in the aorta. The results of the current study indicated that compared with the control group, a large area of AS plaque in the aortic sinus that contained a large amount of red-stained lipids and decreased collagen fiber content were found in the model group, which exhibited higher total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), oxidized low-density lipoprotein (ox-LDL) and MDA levels; higher ALT and AST activities, lower high-density lipoprotein cholesterol (HDL-C) and SOD levels and increased expression levels of PCSK9, LOX-1, p53, p21 and p16. Fisetin is a phytochemical and bioflavonoid that serves a potential role in chronic diseases including AS, obesity, diabetes and cancer due to its wide biological activities, such as regulating lipid metabolism and anti-aging, anti-oxidation and anti-inflammatory. Atorvastatin is recognized as a first-line treatment drug for AS; therefore it was used as a positive control in the current study. Following fisetin and atorvastatin treatment, both the AS plaque and the lipid accumulation in the aortic sinus were significantly reduced, and the expressions of PCSK9, LOX-1 and aging markers, including p53, p21 and p16 were downregulated.

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BRD4 contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake

Cited by 48 publications

References 47 publications

Similarities and interplay between senescent cells and macrophages

Similarities and interplay between senescent cells and macrophages

The BET family in immunity and disease

Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX‑1 in apoE<sup>‑/‑</sup> mice

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