Novel explanation for NSAID induced cardiovascular side effects

Non-steroidal anti-inflammatory drugs (NSAIDS) inhibit cyclooxygenase (COX), the enzymes that reduce prostaglandin production. There are two isoforms, COX-1 which is constitutively expressed, and COX-2 which is inducible. NSAIDS are widely used for their analgesic, antipyretic and anti-inflammatory properties however despite their therapeutic effectiveness, their use has been widely scrutinised due to their tendency to produce side effects. Since prostaglandins protect the gastrointestinal tract and are important in platelet aggregation, NSAID reduction of prostanoids increases the risk of gastrointestinal ulceration and bleeds. Clinical trials revealed the side effects of both pan and COX-1 sparing NSAIDs led to gastrointestinal damage and cardiovascular complications including myocardial infarction. COX-2 selective drugs (such as celecoxib and rofecoxib) were developed to avoid gastrointestinal damage.

While much debate about the CV side effects of NSAIDs has concentrated on the direct effects of NSAIDs on COX activity, this project aims to investigate the indirect CV side effects of NSAIDs and related compounds. This follows on from a pilot study conducted at the University of Hertfordshire where in silico modelling of celecoxib and diclofenac indicated a potential for both drugs to associate with thyroid hormone receptor β (TRβ), and further analysis using in vitro methods indicate that both celecoxib and diclofenac and not naproxen possess TRβ antagonistic properties. This nuclear receptor is of great interest, with clear relationships between hypothyroidism associated with increased heart muscle stiffness and an increased risk of myocardial infarction. 

 

Project timeframe

The project commenced in 2013.

Project aims

  1. Confirm predicted interactions with specific nuclear receptor luciferase reporter assays.
  2. Using in vitro assays, determine whether NSAID interaction with other receptors (as determined by computational chemistry methods) interferes with normal cell function.
  3. Measure effects of NSAIDs in endocrine systems.

Project findings and impact

Output, findings and impact will be updated in due course.

Research team

Dr Louise Mackenzie

Dr Prabel Chatterjee

Output

LS MACKENZIE. Thyroid Hormone Receptor Antagonists; from Environmental Pollution to Novel Small Molecules. THYROID HORMONE (Academic Press/Elsevier) Vitam Horm. 106:147-162 (2018)

Zloh, M., Perez-Diaz, N., Tang, L., Patel, P. & Mackenzie, L.S. Evidence that Diclofenac and Celecoxib are thyroid hormone receptor beta antagonists. Life sciences; 1;146: 66-72 (2016)

Perez-Diaz, N., Zloh, M., Tang, L., Patel, P. & Mackenzie, L.S. Evidence that Diclofenac and Celecoxib are  Thyroid Hormone Receptor Beta Antagonists; use of in silico, molecular and pharmacological techniques. pA2 Online. Vol 13, iss 3, 246 (2015)

Ahmetaj-Shala, B., Kirkby, N. S., Knowles, R., Al'Yamani, M., Mazi, S., Wang, Z., Tucker, A. T., Mackenzie, L. S., Armstrong, P. C. J., Nüsing, R. M., Tomlinson, J. A. P., Warner, T. D., Leiper, J. & Mitchell, J. A. Reply to Letter Regarding Article, "Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine: Novel Explanation of Cardiovascular Side Effects Associated With Anti-Inflammatory Drugs. Circulation. 131, 7, p. 633-42 10 p (2015)

Kirkby, N., Chan, M. V., Lundberg, M. H., MacKenzie, L.S., Leadbeater, P. D. M., Milne, G. L., Potter, C. M., Al-Yamani, M., Adeyemi, O., Warner, T. D. & Mitchell, J. A. Aspirin triggered 15-epi-lipoxin A4 predicts cyclo-oxygenase-2 in the lungs of LPS treated mice but not in the circulation: implications for a clinical test. FASEB Journal. 27, p. 3938-46

Kirkby, N. S., Zaiss, A. K., Urquhart, P., Jiao, J., Austin, P. J., Al-Yamani, M., Lundberg, M. H., MacKenzie, L.S., Warner, T. D., Nicolaou, A., Herschman, H. R. & Mitchell, J. A. LC-MS/MS Confirms That COX-1 Drives Vascular Prostacyclin Whilst Gene Expression Pattern Reveals Non-Vascular Sites of COX-2 Expression. PLoS ONE. 8, 7, e69524

Kirkby, N. S., Lundberg, M. H., Harrington, L. S., Leadbeater, P. D. M., Potter, C. M. F., Al-Yamani, M., Adeyemi, O., Mitchell, J. A., Warner, T. D. & Milne, G. L. Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system. Proceedings of the National Academy of Sciences. 109, 43, p. 17597-17602 6 p. Joint first Author. Erratum in PNAS Jan 2013; 110(4):1561 

Potter, C. M. F., Lundberg, M. H., Harrington, L. S., Moshkov, A. V., Gorelik, J., Mitchell, J. A., Warboys, C. M., Weinberg, P. D., Warner, T. D. & Berson, R. E. Role of shear stress in endothelial cell morphology and expression of cyclooxygenase isoforms. Arteriosclerosis, Thrombosis, and Vascular Biology. 31, 2, p. 384-391 8 p.

Partners

Mr Gary Dolan (University of Hertfordshire)

Emeritus Professor Mire Zloh (University of Hertfordshire)

Dr Lisa Lione (University of Hertfordshire)

Prof Jane Mitchell (Imperial College)

Dr Nick Kirkby (Imperial College)