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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Original data of RNA-sequencing are available from the NCBI Gene Expression Omnibus (GEO) database under accession number GSE185635.
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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).
The authors declare no competing interests.
All animal procedures in this study were approved by the Institutional Review and Ethics Board of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine.
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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 30, 618–631 (2023). https://doi.org/10.1038/s41418-022-01065-1