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
Affiliations
Yang Zhao
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
Yuhao Liu
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Guizhen Zhao
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Haocheng Lu
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
Yaozhong Liu
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Chao Xue
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Ziyi Chang
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Hongyu Liu
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Yongjie Deng
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Wenying Liang
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Huilun Wang
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Oren Rom
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
Minerva T. Garcia-Barrio
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Tianqing Zhu
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Yanhong Guo
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Lin Chang
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Jiandie Lin
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Y. Eugene Chen
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
Jifeng Zhang
Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Corresponding author
Summary: 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.
