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 3

BAF60c preserves VSMC contractile phenotype.

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BAF60c preserves VSMC contractile phenotype. (A–D) HASMCs were infected ...
(A–D) HASMCs were infected with Ad-sh-lacZ and Ad-sh-BAF60c (10 MOI) (A and B) or Ad-GFP and Ad-BAF60c (10 MOI) (C and D). After 48 hours, cells were serum starved in Opti-MEM for 24 hours. mRNA levels of BAF60c, ACTA2, and CNN1 (A and C) and protein abundance of BAF60c, α-actin, and SM22α (B and D) were determined from 6 independent experiments. (E–G) MASMCs were isolated from Baf60cfl/fl and Baf60cSMKO mice 9 days after 5 consecutive days of tamoxifen (75 mg/kg/d) intraperitoneal injection. qPCR (E) and Western blot (F) to determine the expression of Baf60c, Myh11, α-actin, calponin, and SM22α in MASMCs. (G) Representative immunofluorescence images of BAF60c and α-actin staining of MASMCs and quantification of the percentage of spindle-like or polygonal-like cells. Nuclei stained with DAPI are blue. Scale bars: 50 μm. Data are represented as mean ± SEM. Student’s t test for (A–F); χ2 test (G). *P < 0.05.