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Gene Expression Profile of Coronary Artery Cells Treated With Nonsteroidal Anti-inflammatory Drugs Reveals Off-target Effects

Palayoor, Sanjeewani T. PhD*; J-Aryankalayil, Molykutty PhD*; Makinde, Adeola Y. PhD*; Cerna, David PhD*; Falduto, Michael T. PhD; Magnuson, Scott R. PhD; Coleman, C. Norman MD*

Journal of Cardiovascular Pharmacology: June 2012 - Volume 59 - Issue 6 - p 487–499
doi: 10.1097/FJC.0b013e31824ba6b5
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Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) have come under scrutiny because of the gastrointestinal, renal, and cardiovascular toxicity associated with prolonged use of these drugs. The purpose of this study was to identify molecular targets for NSAIDs related to cellular toxicity with a view to optimize drug efficacy in the clinic. Coronary artery smooth muscle cells and endothelial cells were treated with low (clinically achievable) and high (typically used in preclinical studies) concentrations of celecoxib, NS398, and ibuprofen for 24 hours. NSAIDs-induced gene expression changes were evaluated by microarray analysis and validated by real-time reverse-transcription polymerase chain reaction and western blotting. The functional significance of differentially expressed genes was evaluated by Ingenuity Pathway Analysis. At high concentrations, NSAIDs altered the expression of genes regulating cell proliferation and cell death. NSAIDs also altered genes associated with cardiovascular functions including inflammation, thrombosis, fibrinolysis, coronary artery disease, and hypertension. The gene expression was most impacted by ibuprofen, celecoxib, and NS398, in that order. This study revealed that NSAIDs altered expression of an array of genes associated with cardiovascular events and emphasizes the potential for fingerprinting drugs in preclinical studies to assess the potential drug toxicity and to optimize the drug efficacy in clinical settings.

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*Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD

GenUs Biosystems, Inc, Northbrook, IL.

Reprints: Sanjeewani T. Palayoor, PhD, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Building # 10, Room B3B406, Bethesda, MD 20892 (e-mail: palayoor@mail.nih.gov).

Supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org).

Received October 17, 2011

Accepted January 17, 2012

© 2012 Lippincott Williams & Wilkins, Inc.