BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis

Oct 22, 2026

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Abdominal aortic aneurysm (AAA) is a fatal vascular disease with limited therapeutic options. BAF60c, a SWI/SNF chromatin remodeling subunit, is shown to be downregulated in human and mouse AAA tissues, with primary localization to vascular smooth muscle cells (VSMCs). VSMC-specific Baf60c knockout aggravates angiotensin II and elastase-induced AAA, increasing elastin degradation, inflammatory infiltration, phenotypic switching, and apoptosis. Mechanistically, BAF60c preserves contractility via SRF–P300–SWI/SNF association and restrains NF-κB target gene chromatin while promoting KLF5-dependent BCL2 expression, expanding therapeutic potential for AAA.

LanguageEnglish

CategoryHealthcare

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Pages18

Reading Time45 min

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Introduction

Results

BAF60c is reduced in human and murine AAA

The Journal of Clinical Investigation RESEAR CH ARTICLE BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis Guizhen Zhao,1 Yang Zhao,1 Haocheng Lu,1 Ziyi Chang,1 Hongyu Liu,1 Huilun Wang,1 Wenying Liang,1 Yuhao Liu,1 Tianqing Zhu,1 Oren Rom,1,2 Yanhong Guo,1 Lin Chang,1 Bo Yang,3 Minerva T. Garcia-Barrio,1 Jiandie D. Lin,4 Y. Eugene Chen,1 and Jifeng Zhang1 1Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA. 2Department of Pathology and Translational Pathobiology, Louisiana State University Health Science Center–Shreveport, Shreveport, Louisiana, USA. 3Department of Cardiac Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA. 4Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA. Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. BAF60c, a unique subunit of the SWItch/ sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, is critical for cardiac and skeletal myogenesis, yet little is known about its function in the vasculature and, specifically, in AAA pathogenesis. Here, we found that BAF60c was downregulated in human and mouse AAA tissues, with primary staining to vascular smooth muscle cells (VSMCs), confirmed by single-cell RNA-sequencing. In vivo studies revealed that VSMC-specific knockout of Baf60c significantly aggravated both angiotensin II–(Ang II–) and elastase-induced AAA formation in mice, with a significant increase inelastin degradation, inflammatory cell infiltration, VSMC phenotypic switch, and apoptosis. In vitro studies showed that BAF60c knockdown in VSMCs resulted in loss of contractile phenotype, increased VSMC inflammation, and apoptosis. Mechanistically, we demonstrated that BAF60c preserved VSMC contractile phenotype by strengthening serum response factor (SRF) association with its coactivator P300 and the SWI/SNF complex and suppressing VSMC inflammation by promoting a repressive chromatin state of NF-κB target genes as well as preventing VSMC apoptosis through transcriptional activation of KLF5-dependent B cell lymphoma 2 (BCL2) expression. Our identification of the essential role of BAF60c in preserving VSMC homeostasis expands its therapeutic potential in preventing and treating AAA. Introduction Abdominal aortic aneurysm (AAA) is one of the leading causes of death in developed countries, with an overall mortality rate of approximately 90% in case of rupture (1). AAA usually affects the infrarenal aorta and is typically associated with well-recognized risk factors, including aging, smoking, male sex, hypertension, and atherosclerosis (2) . Vascular smooth muscle cells (VSMCs) are critical to maintaining the integrity of healthy vessels, yet retain remarkable plasticity in response to environmental stimuli. Although VSMC dysfunction, including apoptosis and phenotypic switch, have been shown to contribute to AAA development (3–5), the precise control of these processes at the chromatin level remains largely unexplored. Without effective pharmacological therapy available for AAA so far, the current clinical interventions are limited to surgical or endovascular repairs, with only 10% of AAA patients eligible (1, 6). This is likely due to the incomplete understanding of the molecular mechanisms underlying AAA development. Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2022, Zhao et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: January 10, 2022; Accepted: September 1, 2022; Published: November 1, 2022. Reference information: J Clin Invest. 2022;132(21):e158309 . [https://doi.org/10.1172/JCI158309](https://doi.org/10.1172/JCI158309) . The SWItch/sucrose nonfermentable (SWI/SNF) chromat

FAQs

What is BAF60c and what role does it play in AAA development?

BAF60c is a SWI/SNF chromatin remodeling subunit. It is downregulated in AAA tissues and its loss worsens AAA, indicating a protective role through VSMC homeostasis.

How does VSMC-specific knockout of Baf60c affect aneurysm formation in mice?

VSMC-specific Baf60c knockout significantly aggravates angiotensin II and elastase-induced AAA, with increased elastin degradation, inflammatory infiltration, phenotypic switching, and apoptosis.

What mechanisms explain how BAF60c preserves VSMC function?

BAF60c strengthens SRF association with P300 and the SWI/SNF complex to maintain contractile phenotype, suppresses inflammation by promoting a repressive chromatin state of NF-κB target genes, and prevents apoptosis via KLF5-dependent BCL2 transcriptional activation.

Oct 22, 2026

Uploaded by OKfine