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Volume 2011 (2011), Article ID 503028, 8 pages
Review Article

Methotrexate in Atherogenesis and Cholesterol Metabolism

1Department of Medicine, Division of Translational Medicine, New York University School of Medicine, NBV 16N1, 550 First Avenue, New York, NY 10016, USA
2Inflammation Section, Winthrop Research Institute, Department of Medicine, Winthrop University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501-3893, USA

Received 15 October 2010; Revised 11 January 2011; Accepted 11 January 2011

Academic Editor: M. Jauhiainen

Copyright © 2011 Eric Coomes et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Methotrexate is a disease-modifying antirheumatic drug commonly used to treat inflammatory conditions such as rheumatoid arthritis which itself is linked to increased cardiovascular risk. Treatments that target inflammation may also impact the cardiovascular system. While methotrexate improves cardiovascular risk, inhibition of the cyclooxygenase (COX)-2 enzyme promotes atherosclerosis. These opposing cardiovascular influences may arise from differing effects on the expression of proteins involved in cholesterol homeostasis. These proteins, ATP-binding cassette transporter (ABC) A1 and cholesterol 27-hydroxylase, facilitate cellular cholesterol efflux and defend against cholesterol overload. Methotrexate upregulates expression of cholesterol 27-hydroxylase and ABCA1 via adenosine release, while COX-2 inhibition downregulates these proteins. Adenosine, acting through the A2A and A3 receptors, may upregulate proteins involved in reverse cholesterol transport by cAMP-PKA-CREB activation and STAT inhibition, respectively. Elucidating underlying cardiovascular mechanisms of these drugs provides a framework for developing novel cardioprotective anti-inflammatory medications, such as selective A2A receptor agonists.