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.
Gomez D, Owens GK. Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc Res. 2012;95:156–64.
Ailawadi G, Moehle CW, Pei H, Walton SP, Yang Z, Kron IL, et al. Smooth muscle phenotypic modulation is an early event in aortic aneurysms. J Thorac Cardiovasc Surg. 2009;138:1392–9.
Brozovich FV, Nicholson CJ, Degen CV, Gao YZ, Aggarwal M, Morgan KG. Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders. Pharm Rev. 2016;68:476–532.
Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004;84:767–801.
Hulsmans M, Nahrendorf M. Proliferative, degradative smooth muscle cells promote aortic disease. J Clin Invest. 2020;130:1096–8.
Alexander MR, Owens GK. Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annu Rev Physiol. 2012;74:13–40.
Wang Z, Wang DZ, Hockemeyer D, McAnally J, Nordheim A, Olson EN. Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature 2004;428:185–9.
Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, et al. Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation 2013;128:2047–57.
Wirka RC, Wagh D, Paik DT, Pjanic M, Nguyen T, Miller CL, et al. Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nat Med. 2019;25:1280–9.
Mottis A, Mouchiroud L, Auwerx J. Emerging roles of the corepressors NCoR1 and SMRT in homeostasis. Genes Dev. 2013;27:819–35.
Yamamoto H, Williams EG, Mouchiroud L, Canto C, Fan W, Downes M, et al. NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 2011;147:827–39.
Li P, Spann NJ, Kaikkonen MU, Lu M, Oh DY, Fox JN, et al. NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. Cell 2013;155:200–14.
Oppi S, Nusser-Stein S, Blyszczuk P, Wang X, Jomard A, Marzolla V, et al. Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARgamma signature. Eur Heart J. 2020;41:995–1005.
Li C, Sun XN, Chen BY, Zeng MR, Du LJ, Liu T, et al. Nuclear receptor corepressor 1 represses cardiac hypertrophy. EMBO Mol Med. 2019;11:e9127.
Du LJ, Sun JY, Zhang WC, Wang YL, Zhu H, Liu T, et al. Macrophage NCOR1 deficiency ameliorates myocardial infarction and neointimal hyperplasia in mice. J Am Heart Assoc. 2020;9:e015862.
Kuhbandner S, Brummer S, Metzger D, Chambon P, Hofmann F, Feil R. Temporally controlled somatic mutagenesis in smooth muscle. Genesis 2000;28:15–22.
Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res. 2006;98:322–34.
Mack CP, Somlyo AV, Hautmann M, Somlyo AP, Owens GK. Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization. J Biol Chem. 2001;276:341–7.
El-Hamamsy I, Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol. 2009;6:771–86.
Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39.
Li G, Wang M, Caulk AW, Cilfone NA, Gujja S, Qin L, et al. Chronic mTOR activation induces a degradative smooth muscle cell phenotype. J Clin Invest. 2020;130:1233–51.
Parmacek MS. Myocardin-related transcription factors: critical coactivators regulating cardiovascular development and adaptation. Circ Res. 2007;100:633–44.
Creemers EE, Sutherland LB, McAnally J, Richardson JA, Olson EN. Myocardin is a direct transcriptional target of Mef2, Tead and Foxo proteins during cardiovascular development. Development 2006;133:4245–56.
Nott A, Cheng J, Gao F, Lin YT, Gjoneska E, Ko T, et al. Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat Neurosci. 2016;19:1497–505.
Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A. Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci USA. 2005;102:11278–83.
Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, et al. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med. 2003;9:1506–12.
Patel J, Chuaiphichai S, Douglas G, Gorvin CM, Channon KM. Vascular wall regulator of G-protein signalling-1 (RGS-1) is required for angiotensin II-mediated blood pressure control. Vasc Pharm. 2018;108:15–22.
Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005;5:472–84.
Chan CM, Macdonald CD, Litherland GJ, Wilkinson DJ, Skelton A, Europe-Finner GN, et al. Cytokine-induced MMP13 expression in human chondrocytes is dependent on activating Transcription Factor 3 (ATF3) Regulation. J Biol Chem. 2017;292:1625–36.
Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995;75:487–517.
Liu ZP, Wang Z, Yanagisawa H, Olson EN. Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Dev Cell. 2005;9:261–70.
Yang X, Gong Y, Tang Y, Li H, He Q, Gower L, et al. Spry1 and Spry4 differentially regulate human aortic smooth muscle cell phenotype via Akt/FoxO/myocardin signaling. PLoS One. 2013;8:e58746.
Halterman JA, Kwon HM, Zargham R, Bortz PD, Wamhoff BR. Nuclear factor of activated T cells 5 regulates vascular smooth muscle cell phenotypic modulation. Arterioscler Thromb Vasc Biol. 2011;31:2287–96.
Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4:E131–6.
Ogawa S, Lozach J, Jepsen K, Sawka-Verhelle D, Perissi V, Sasik R, et al. A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. Proc Natl Acad Sci USA. 2004;101:14461–6.
Li P, Fan W, Xu J, Lu M, Yamamoto H, Auwerx J, et al. Adipocyte NCoR knockout decreases PPARgamma phosphorylation and enhances PPARgamma activity and insulin sensitivity. Cell 2011;147:815–26.
Wang J, He N, Zhang N, Quan D, Zhang S, Zhang C, et al. NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection. Nat Commun. 2017;8:959.
Perissi V, Jepsen K, Glass CK, Rosenfeld MG. Deconstructing repression: evolving models of co-repressor action. Nat Rev Genet. 2010;11:109–23.
Liu B, Granville DJ, Golledge J, Kassiri Z. Pathogenic mechanisms and the potential of drug therapies for aortic aneurysm. Am J Physiol Heart Circ Physiol. 2020;318:H652–H70.
Liu R, Lo L, Lay AJ, Zhao Y, Ting KK, Robertson EN, et al. ARHGAP18 protects against thoracic aortic aneurysm formation by mitigating the synthetic and proinflammatory smooth muscle cell phenotype. Circ Res. 2017;121:512–24.
Nogi M, Satoh K, Sunamura S, Kikuchi N, Satoh T, Kurosawa R, et al. Small GTP-binding protein GDP dissociation stimulator prevents thoracic aortic aneurysm formation and rupture by phenotypic preservation of aortic smooth muscle cells. Circulation 2018;138:2413–33.
Guo X, Shi N, Cui XB, Wang JN, Fukui Y, Chen SY. Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling. Circ Res. 2015;116:e71–80.
Grant CE, Bailey TL, Noble WS. FIMO: scanning for occurrences of a given motif. Bioinformatics 2011;27:1017–8.
de Carcer G, Wachowicz P, Martinez-Martinez S, Oller J, Mendez-Barbero N, Escobar B, et al. Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis. Nat Med. 2017;23:964–74.
Ito H, Morishita R, Nagata KI. Functions of Rhotekin, an effector of Rho GTPase, and its binding partners in mammals. Int J Mol Sci. 2018;19:2121.
Sun XN, Li C, Liu Y, Du LJ, Zeng MR, Zheng XJ, et al. T-cell mineralocorticoid receptor controls blood pressure by regulating interferon-gamma. Circ Res. 2017;120:1584–97.
Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000;105:1605–12.
Satoh K, Nigro P, Matoba T, O’Dell MR, Cui Z, Shi X, et al. Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat Med. 2009;15:649–56.
Hadi T, Boytard L, Silvestro M, Alebrahim D, Jacob S, Feinstein J, et al. Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. Nat Commun. 2018;9:5022.
Krege JH, Hodgin JB, Hagaman JR, Smithies O. A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension 1995;25:1111–5.
Handoko ML, Schalij I, Kramer K, Sebkhi A, Postmus PE, van der Laarse WJ, et al. A refined radio-telemetry technique to monitor right ventricle or pulmonary artery pressures in rats: a useful tool in pulmonary hypertension research. Pflug Arch. 2008;455:951–9.
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 (2022). https://doi.org/10.1038/s41418-022-01065-1