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NCOR1 maintains the homeostasis of vascular smooth muscle cells and protects against aortic aneurysm

Abstract

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays critical roles in the pathogenesis of aortic aneurysm (AA). The function of nuclear receptor corepressor1 (NCOR1) in regulation of VSMC phenotype and AA is unclear. Herein, using smooth muscle NCOR1 knockout mice, we demonstrated that smooth muscle NCOR1 deficiency decreased both mRNA and protein levels of contractile genes, impaired stress fibers formation and RhoA pathway activation, reduced synthesis of elastin and collagens, and induced the expression and activity of MMPs, manifesting a switch from contractile to degradative phenotype of VSMCs. NCOR1 modulated VSMC phenotype through 3 different mechanisms. First, NCOR1 deficiency increased acetylated FOXO3a to inhibit the expression of Myocd, which downregulated contractile genes. Second, deletion of NCOR1 derepressed NFAT5 to induce the expression of Rgs1, thus impeding RhoA activation. Third, NCOR1 deficiency increased the expression of Mmp12 and Mmp13 by derepressing ATF3. Finally, a mouse model combined apoE knockout mice with angiotensin II was used to study the role of smooth muscle NCOR1 in the development of AA. The results showed that smooth muscle NCOR1 deficiency increased the incidence of aortic aneurysms and exacerbated medial degeneration in angiotensin II-induced AA mouse model. Collectively, our data illustrated that NCOR1 interacts with FOXO3a, NFAT5, and ATF3 to maintain contractile phenotype of VSMCs and suppress AA development. Manipulation of smooth muscle NCOR1 may be a potential approach for AA treatment.

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Fig. 1: Deficiency of nuclear receptor corepressor 1 (NCOR1) downregulates contractile genes in vascular smooth muscle cells (VSMCs).
Fig. 2: Deficiency of NCOR1 impairs RhoA signaling pathway in VSMCs.
Fig. 3: Deficiency of NCOR1 promotes degradation of extracellular matrix in VSMCs.
Fig. 4: FOXO3a mediates the impacts of NCOR1 deficiency on contractile genes.
Fig. 5: NFAT5 mediates the impacts of NCOR1 deficiency on RhoA activation in VSMCs.
Fig. 6: ATF3 mediates the impacts of NCOR1 deficiency on Mmp12 and Mmp13 expression in VSMCs.
Fig. 7: Deficiency of smooth muscle NCOR1 exacerbates aortic aneurysm in mice.

Data availability

Original data of RNA-sequencing are available from the NCBI Gene Expression Omnibus (GEO) database under accession number GSE185635.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81725003, 81991503, 81991500, 81921002, 31900810, 81900227, 82100446), the China Postdoctoral Science Foundation (2018M640402), and the Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20212500).

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L-JD, J-YS, W-CZ, YL, YL, W-ZL, TL, HZ, Y-LW, SS, L-JZ, and B-YC performed the experiments and acquisition of data; L-JD, J-YS and W-CZ designed the experiments and analyzed the data; L-JD, HL, R-GL, FJ, and S-ZD wrote and revised the manuscripts; R-GL, FJ, and S-ZD supervised the study.

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Correspondence to Ruo-Gu Li, Feng Jia or Sheng-Zhong Duan.

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Du, LJ., Sun, JY., Zhang, WC. et al. NCOR1 maintains the homeostasis of vascular smooth muscle cells and protects against aortic aneurysm. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01065-1

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