Research Paper Volume 12, Issue 10 pp 9240—9259
BRD4 contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake
- 1 Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China
- 2 Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- 3 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
- 4 Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
Received: December 21, 2019 Accepted: March 9, 2020 Published: May 11, 2020https://doi.org/10.18632/aging.103200
How to Cite
Copyright © 2020 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.