2. Academic Validation
  3. NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment

NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment

  • Cell Mol Life Sci. 2021 Feb;78(4):1709-1727. doi: 10.1007/s00018-020-03607-7.
Yutong Miao  # 1,  Yang Zhao  # 2,  Lulu Han 1,  Xiaolong Ma 1,  Jiacheng Deng 3,  Juan Yang 1,  Silin Lü 4,  Fangyu Shao 1,  Wei Kong 1,  Wengong Wang 5,  Qingbo Xu 3,  Xian Wang 6,  Juan Feng 7
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China.
  • 2 Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People's Republic of China.
  • 3 Cardiovascular Division, BHF Center for Vascular Regeneration, King's College London, London, UK.
  • 4 State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
  • 5 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Beijing, People's Republic of China.
  • 6 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China. xwang@bjmu.edu.cn.
  • 7 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China. juanfeng@bjmu.edu.cn.
  • # Contributed equally.
PMID: 32734582 DOI: 10.1007/s00018-020-03607-7
Abstract

Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA Sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic Enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially Autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to Integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.

Keywords

ATX; Abdominal aortic aneurysm; Endothelial cells; NSun2; T cells.

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