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Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo

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اقرأ أكثر حفظ في قائمتي
  • المؤلفون: UCH. Departamento de Medicina y Cirugía; Producción Científica UCH 2022; Yeh, Chih-Fan; Cheng, Shih-Hsin; Lin, Yu-Shan; Shentu, Tzu-Pin; Huang, Ru-Ting; Zhu, Jiayu; García Fernández, Francisca
  • نوع التسجيلة:
    Electronic Resource
  • الدخول الالكتروني :
    http://hdl.handle.net/10637/14444
    https://doi.org/10.1126/sciadv.abl8096
    Science Advances, vol. 8, i. 3 (21 jan. 2022)
    Este artículo de investigación ha sido financiado por becas del Taiwan Ministry of Science Technology (108-2314-B-002-199-MY3 y 109-2628-B-002-032), del Taiwan National Health Research Institute (NHRI-EX109-10936SI), del CRC Translational Research (IBMS-CRC108-P03), del Institute of Biomedical Sciences at Academia Sinica, Taiwan (AS-TM-109-01-04), del National Taiwan University Hospital (NTUH.107-T02, UN107-019, 107-N4062, VN107-03, 108-T16, VN108-06, VN109-07, VN110-01, NTUH.108-P04, 108-N4198, 108-S4247, 108-EDN03, 109-EDN05, 109-S4576, 110-S4836 y 110-T16), del National Taiwan University College of Medicine and National Taiwan University Hospital (NSCCMOH-131-41, 109C101-41 y 110C101-071), de la National Taiwan University (109L7872), así como del Chicago Biomedical Consortium (A-014), de la American Heart Association (20TPA35490401) y del National Institutes of Health (NIH R01HL138223, R01HL136765, R01HL119798 y R01HL139757).
  • معلومة اضافية
    • Publisher Information:
      American Association for the Advancement of Science 2022-01-21
    • نبذة مختصرة :
      Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE−/− mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in ApoE−/− mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis.
    • الموضوع:
      Atherosclerosis.; Ateroesclerosis.; Molecular biology.; Proteínas.; Proteins.; Biología molecular.; Artículo
    • Availability:
      Open access content. Open access content
      https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
      open access
    • Note:
      English
    • Other Numbers:
      ESRIC oai:repositorioinstitucional.ceu.es:10637/14444
      Yeh, C. F., Cheng, S. H., Lin, Y. S., Shentu, T. P., Huang, R. T., Zhu, J., Chen, Y. T., Kumar, S., Lin, M. S., Kao, H. L., Huang, P. H., Roselló-Sastre, E., Garcia, F., Jo, H., Fang, Y. & Yang, K. C. (2022). Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo. Science Advances, vol. 8, i. 3 (21 jan.), art. eabl8096. DOI: https://doi.org/10.1126/sciadv.abl8096
      2375-2548 (Electrónico)
      1477927688
    • Contributing Source:
      REPOSITORIO INSTITUCIONAL CEU
      From OAIster®, provided by the OCLC Cooperative.
    • الرقم المعرف:
      edsoai.on1477927688
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