1. Academic Validation
  2. NCOR1 maintains the homeostasis of vascular smooth muscle cells and protects against aortic aneurysm

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

  • Cell Death Differ. 2022 Sep 23. doi: 10.1038/s41418-022-01065-1.
Lin-Juan Du  # 1 2 Jian-Yong Sun  # 1 2 Wu-Chang Zhang  # 1 2 Yuan Liu 1 2 Yan Liu 1 2 Wen-Zhen Lin 1 2 Ting Liu 1 2 Hong Zhu 1 2 Yong-Li Wang 3 Shuai Shao 4 Lu-Jun Zhou 1 2 Bo-Yan Chen 1 2 Hongjian Lu 5 Ruo-Gu Li 6 Feng Jia 7 8 Sheng-Zhong Duan 9 10 11
Affiliations

Affiliations

  • 1 Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China.
  • 2 National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
  • 3 Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
  • 4 Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 5 Department of Rehabilitation, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu, 226001, China.
  • 6 Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. [email protected].
  • 7 Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. [email protected].
  • 8 Department of Neurosurgery, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu, 226001, China. [email protected].
  • 9 Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China. [email protected].
  • 10 National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China. [email protected].
  • 11 Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
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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