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Cartilage oligomeric matrix protein fine-tunes disturbed flow-induced endothelial activation and atherogenesis.
Lv, Huizhen; Wang, Hui; Quan, Meixi; Zhang, Chenghu; Fu, Yi; Zhang, Lu; Lin, Changdong; Liu, Xin; Yi, Xianfu; Chen, Jianfeng; Wang, Xiujie; Cheng, Tao; Ai, Ding; Kong, Wei; Zhu, Yi.
Afiliación
  • Lv H; State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; State Key Laboratory of
  • Wang H; State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • Quan M; State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • Zhang C; State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • Fu Y; Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
  • Zhang L; Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
  • Lin C; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • Liu X; Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China.
  • Yi X; School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China.
  • Chen J; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • Wang X; Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China.
  • Cheng T; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
  • Ai D; State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; State Key Laboratory of
  • Kong W; Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
  • Zhu Y; State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address: zhuy
Matrix Biol ; 95: 32-51, 2021 01.
Article en En | MEDLINE | ID: mdl-33068727
Disturbed flow leads to increased inflammatory responses of endothelial cells (ECs) prone to atherogenic state. Currently, little is known about the physiological mechanisms protecting vasculature against disturbed flow-activated ECs leading to atherosclerosis. Understanding the protective mediators involved in EC activation could provide novel therapeutic strategies for atherosclerosis. The extracellular matrix microenvironment profoundly regulates cellular homeostasis. A non-EC resident ECM protein, cartilage oligomeric matrix protein (COMP), has diverse protective roles in the cardiovascular system. To determine whether COMP could protect against disturbed flow-activated EC and atherosclerosis, we compared oscillatory shear stress (OSS) induced EC activation coated with various ECM proteins. Purified COMP inhibited EC activation caused by OSS. EC activation was upregulated in the aortic arch where the flow is disturbed in COMP-/- mice as compared with wild-type mice under physiological conditions or pathologically in partially ligated mouse carotid arteries. Mechanistically, co-immunoprecipitation, mammalian two-hybrid and FRET assay results suggest that COMP bound directly to integrin α5 via its C-terminus. We next synthesized a COMP-derived peptidomimetics (CCPep24) mimicking a specific COMP-integrin α5 interaction and found that CCPep24 protected against EC activation and atherogenesis in vivo. This study extends our current understanding of how ECM and flow coordinately fine-tune EC homeostasis and reveals the potential therapeutic effect of COMP or COMP-derived peptidomimetics on blocking aberrant integrin α5 activation, inflammatory EC activation and atherosclerosis pathogenesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Integrina alfa5 / Aterosclerosis / Proteína de la Matriz Oligomérica del Cartílago Límite: Animals / Humans Idioma: En Revista: Matrix Biol Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2021 Tipo del documento: Article Pais de publicación: Países Bajos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Integrina alfa5 / Aterosclerosis / Proteína de la Matriz Oligomérica del Cartílago Límite: Animals / Humans Idioma: En Revista: Matrix Biol Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2021 Tipo del documento: Article Pais de publicación: Países Bajos