Methotrexate attenuates vascular inflammation through an adenosine-microRNA dependent pathway
- Brigham and Women's Hospital/Harvard Medical School, United States
- Central South University, China
- Xiangya Hospital, Central South University, China
- 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
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
- Peter Tontonoz, University of California, Los Angeles, United States
Version history
- Received: April 20, 2020
- Accepted: December 31, 2020
- Accepted Manuscript published: January 8, 2021 (version 1)
- 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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Methotrexate attenuates vascular inflammation through an adenosine-microRNA dependent pathway
eLife 10:e58064.
https://doi.org/10.7554/eLife.58064
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