BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis
Guizhen Zhao, … , Y. Eugene Chen, Jifeng Zhang
Guizhen Zhao, … , Y. Eugene Chen, Jifeng Zhang
Published September 6, 2022
Citation Information: J Clin Invest. 2022;132(21):e158309. https://doi.org/10.1172/JCI158309.
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Research Article Vascular biology

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

Abstract

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 in elastin 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.

Authors

Guizhen Zhao, Yang Zhao, Haocheng Lu, Ziyi Chang, Hongyu Liu, Huilun Wang, Wenying Liang, Yuhao Liu, Tianqing Zhu, Oren Rom, Yanhong Guo, Lin Chang, Bo Yang, Minerva T. Garcia-Barrio, Jiandie D. Lin, Y. Eugene Chen, Jifeng Zhang

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Figure 1

BAF60c is reduced in human and murine AAA tissues.

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BAF60c is reduced in human and murine AAA tissues. (A) BAF60c, ACTA2 (en...
(A) BAF60c, ACTA2 (encoding α-actin), and TAGLN (encoding SM22α) mRNA levels, relative to GAPDH, were determined by qPCR in human AAA and normal abdominal aortas (AA) (n = 12/group). (B) Protein abundance of BAF60c, SM α-actin, calponin, and SM22α were determined by Western blot in human AAA samples and normal abdominal aortas (n = 5/group). (C) Representative immunofluorescence staining and quantification of BAF60c (red) and SM22α (green) in human AAA and normal abdominal aortas (n = 6/group). Nuclei stained with DAPI are blue. Scale bars: 20 μm. (D) BAF60c in the suprarenal abdominal aortas of C57BL/6J mice injected intraperitoneally with AAV-Pcsk9.D377Y and infused with saline or Ang II (1000 ng/kg/min) for 28 days was determined by Western blot (n = 6/group). (E) BAF60c in the infrarenal abdominal aortas of C57BL/6J mice was determined by Western blot 14 days after elastase exposure or heat-inactivated elastase exposure for 30 minutes (n = 4/group). Data are represented as mean ± SEM. Student’s t test (A–E).