Methotrexate attenuates vascular inflammation through an adenosine-microRNA dependent pathway

  1. Dafeng Yang
  2. Stefan Haemmig
  3. Haoyang Zhou
  4. Daniel Pérez-Cremades
  5. Xinghui Sun
  6. Lei Chen
  7. Jie Li
  8. Jorge Haneo-Mejia
  9. Tianlun Yang
  10. Ivana Hollan
  11. Mark W Feinberg  Is a corresponding author
  1. Brigham and Women's Hospital/Harvard Medical School, United States
  2. Central South University, China
  3. Xiangya Hospital, Central South University, China
  4. University of Pennsylvania, United States

Abstract

Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b (MiR-181b) is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti-inflammatory effects in the vascular endothelium by targeting and activating MiR-181b expression. Both systemic and endothelial-specific MiR-181a2b2-deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a MiR-181a2b2-dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4-MiR-181b signaling cascade. These findings establish an essential role of endothelial MiR-181b in controlling vascular inflammation and that restoring MiR-181b in ECs by high dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.

Data availability

Source data files have been provided for Figures 1 -2. RNA-Seq data has been made accessible.

Article and author information

Author details

  1. Dafeng Yang

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Stefan Haemmig

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Haoyang Zhou

    Cardiovascular, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Daniel Pérez-Cremades

    Medicine, Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xinghui Sun

    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lei Chen

    Cardiology, Xiangya Hospital, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jie Li

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jorge Haneo-Mejia

    Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Tianlun Yang

    Cardiology, Xiangya Hospital, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Ivana Hollan

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Mark W Feinberg

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    For correspondence
    mfeinberg@bwh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9523-3859

Funding

National Institutes of Health (HL115141)

  • Mark W Feinberg

National Institutes of Health (HL134849)

  • Mark W Feinberg

American Heart Association (18SFRN33900144)

  • Mark W Feinberg

American Heart Association (18POST34030395)

  • Stefan Haemmig

Falk Foundation

  • Mark W Feinberg

National Natural Science Foundation of China

  • Tianlun Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were maintained under SPF conditions at an American Association for the Accreditation of Laboratory Animal Care-accredited animal facility at the Brigham and Women's Hospital (protocol #2016N000182). All animal protocols were approved by the Institutional Animal Care and Use Committee at Harvard Medical School, Boston, MA and conducted in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals.

Reviewing Editor

  1. Peter Tontonoz, University of California, Los Angeles, United States

Publication history

  1. Received: April 20, 2020
  2. Accepted: December 31, 2020
  3. Accepted Manuscript published: January 8, 2021 (version 1)
  4. Version of Record published: January 27, 2021 (version 2)

Copyright

© 2021, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Dafeng Yang
  2. Stefan Haemmig
  3. Haoyang Zhou
  4. Daniel Pérez-Cremades
  5. Xinghui Sun
  6. Lei Chen
  7. Jie Li
  8. Jorge Haneo-Mejia
  9. Tianlun Yang
  10. Ivana Hollan
  11. Mark W Feinberg
(2021)
Methotrexate attenuates vascular inflammation through an adenosine-microRNA dependent pathway
eLife 10:e58064.
https://doi.org/10.7554/eLife.58064
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