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

Aging (Albany NY). 2020 May 11;12(10):9240-9259. doi: 10.18632/aging.103200. Epub 2020 May 11.

Abstract

Aging is closely associated with atherosclerosis. Macrophages accumulate in atherosclerotic lesions contributing to the development and progression of atherosclerosis. Although atherosclerotic lesions are known to contain senescent cells, the mechanism underlying the formation of senescent macrophages during atherosclerosis is still unclear. In this study, macrophages with different origins were collected, including THP-1 macrophages, telomerase reverse transcriptase knock out (Tert-/-) mouse peritoneal macrophages, and human peripheral blood mononuclear cells (PBMCs). We found Lipopolysaccharide (LPS) could induce the formation of senescent macrophages, which was typified by the morphological changes, senescence-associated secretory phenotype (SASP) secretory, and persistent DNA damage response. Mechanistically, bromodomain-containing protein 4 (BRD4), a chromosomal binding protein related to gene expression, was found to play a key role in the pathological process, which could offer new therapeutic perspectives. Inhibition of BRD4 by siBRD4 or inhibitors such as JQ-1 or I-BET762 prevented the aging of macrophages and lipid accumulation in the LPS-induced senescent macrophages by decreasing expression of SASP in autocrine and paracrine senescence. These findings have significant implications for the understanding of the pathobiology of age-associated diseases and may guide future studies on targeted clinical drug therapy.

Keywords: BRD4; gene expression; inflammation; macrophage; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Cellular Senescence / drug effects*
  • Humans
  • Lipid Metabolism / drug effects*
  • Lipopolysaccharides / adverse effects
  • Macrophages* / drug effects
  • Macrophages* / metabolism
  • Mice
  • Nuclear Proteins / metabolism*
  • Transcription Factors / metabolism*

Substances

  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • Lipopolysaccharides
  • Nuclear Proteins
  • Transcription Factors