The Cardiovascular Inflammation Reduction Trial (CIRT) was designed to assess whether low-dose methotrexate (LD-MTX) would reduce future cardiac events in patients with metabolic syndrome or type 2 diabetes (T2DM) who are post-myocardial infarction (MI) or have multivessel disease. Our previous work indicates that MTX confers atheroprotection via adenosine A2A receptor (A2AR) activation. In order for A2AR ligation to reduce cardiovascular events, A2AR levels would need to be preserved during MTX treatment. This study was conducted to determine whether LD-MTX alters peripheral blood mononuclear cell (PBMC) adenosine receptor expression in persons at risk for cardiovascular events. Post-MI T2DM CIRT patients were randomized to LD-MTX or placebo (n=10/group). PBMC isolated from blood drawn at enrollment and after 6 weeks were evaluated for expression of adenosine receptors and reverse cholesterol transporters by real-time PCR. Fold change between time points was calculated using factorial analyses of variance. Compared with placebo, the LD-MTX group exhibited a trend toward an increase in A2AR (p=0.06), while A3R expression was significantly decreased (p=0.01) after 6 weeks. Cholesterol efflux gene expression did not change significantly. Persistence of A2AR combined with A3R downregulation indicates that failure of MTX to be atheroprotective in CIRT was not due to loss of adenosine receptors on PBMC (ClinicalTrials.gov identifier: NCT01594333).
- Myocardial Infarction
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Contributors Conceptualization: ABR and JDL. Methodology: ABR, JDL, SA and SEC. Validation: LK, IT. Formal analysis: LK, IT. Data curation: IT and SA. Writing—original draft preparation: IT, ABR. Writing—review and editing: ABR, JDL and SA. Supervision: ABR. Project administration: ABR, JDL. Funding acquisition: ABR. All authors have read and agreed to the published version of the manuscript.
Funding This work was supported by the American Heart Association Grant 16GRNT26430041 (ABR).
Competing interests Allison Reiss is an Editorial Board Member and Joshua De Leon is an Associate Editor for the Journal of Investigative Medicine. No other competing interests declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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