Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis

Yang Zhao; Yuhao Liu; Guizhen Zhao; Haocheng Lu; Yaozhong Liu; Chao Xue; Ziyi Chang; Hongyu Liu; Yongjie Deng; Wenying Liang; Huilun Wang; Oren Rom; Minerva T Garcia-Barrio; Tianqing Zhu; Yanhong Guo; Lin Chang; Jiandie Lin; Y Eugene Chen; Jifeng Zhang

doi:10.1016/j.celrep.2023.113171

Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis

Cell Rep. 2023 Oct 31;42(10):113171. doi: 10.1016/j.celrep.2023.113171. Epub 2023 Sep 27.

Authors

Yang Zhao¹, Yuhao Liu², Guizhen Zhao², Haocheng Lu³, Yaozhong Liu², Chao Xue², Ziyi Chang², Hongyu Liu², Yongjie Deng², Wenying Liang², Huilun Wang², Oren Rom⁴, Minerva T Garcia-Barrio², Tianqing Zhu², Yanhong Guo², Lin Chang², Jiandie Lin⁵, Y Eugene Chen¹, Jifeng Zhang⁶

Affiliations

¹ Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
³ Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Pharmacology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
⁴ Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Pathology and Translational Pathobiology, Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA 71103, USA.
⁵ Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
⁶ Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Electronic address: jifengz@umich.edu.

Abstract

Atherosclerosis, a leading health concern, stems from the dynamic involvement of immune cells in vascular plaques. Despite its significance, the interplay between chromatin remodeling and transcriptional regulation in plaque macrophages is understudied. We discovered the reduced expression of Baf60a, a component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, in macrophages from advanced plaques. Myeloid-specific Baf60a deletion compromised mitochondrial integrity and heightened adhesion, apoptosis, and plaque development. BAF60a preserves mitochondrial energy homeostasis under pro-atherogenic stimuli by retaining nuclear respiratory factor 1 (NRF1) accessibility at critical genes. Overexpression of BAF60a rescued mitochondrial dysfunction in an NRF1-dependent manner. This study illuminates the BAF60a-NRF1 axis as a mitochondrial function modulator in atherosclerosis, proposing the rejuvenation of perturbed chromatin remodeling machinery as a potential therapeutic target.

Keywords: CP: Metabolism; CP: Molecular biology; SWI/SNF; atherosclerosis; chromatin remodeling; macrophage; mitochondria.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Atherosclerosis* / genetics
Chromatin Assembly and Disassembly
Gene Expression Regulation
Homeostasis
Humans
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Transcription Factors
SMARCD1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding