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Int. J. Mol. Sci. 2015, 16(5), 11178-11195; doi:10.3390/ijms160511178

Clonal Expansion of T Cells in Abdominal Aortic Aneurysm: A Role for Doxycycline as Drug of Choice?

Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK
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Academic Editors: Jonathan Golledge and Joseph V. Moxon
Received: 7 November 2014 / Accepted: 5 February 2015 / Published: 18 May 2015
(This article belongs to the Special Issue Advances in Peripheral Artery Disease)
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Abstract

Most reported studies with animal models of abdominal aortic aneurysm (AAA) and several studies with patients have suggested that doxycycline favourably modifies AAA; however, a recent large long-term clinical trial found that doxycycline did not limit aneurysm growth. Thus, there is currently no convincing evidence that doxycycline reduces AAA expansion. Here, we critically review the available experimental and clinical information about the effects of doxycycline when used as a pharmacological treatment for AAA. The view that AAA can be considered an autoimmune disease and the observation that AAA tissue shows clonal expansion of T cells is placed in the light of the well-known inhibition of mitochondrial protein synthesis by doxycycline. In T cell leukaemia animal models, this inhibitory effect of the antibiotic has been shown to impede T cell proliferation, resulting in complete tumour eradication. We suggest that the available evidence of doxycycline action on AAA is erroneously ascribed to its inhibition of matrix metalloproteinases (MMPs) by competitive binding of the zinc ion co-factor. Although competitive binding may explain the inhibition of proteolytic activity, it does not explain the observed decreases of MMP mRNA levels. We propose that the observed effects of doxycycline are secondary to inhibition of mitochondrial protein synthesis. Provided that serum doxycycline levels are kept at adequate levels, the inhibition will result in a proliferation arrest, especially of clonally expanding T cells. This, in turn, leads to the decrease of proinflammatory cytokines that are normally generated by these cells. The drastic change in cell type composition may explain the changes in MMP mRNA and protein levels in the tissue samples. View Full-Text
Keywords: abdominal aortic aneurysm (AAA); clonal expansion; doxycycline; drug target; matrix metalloproteinases; mitochondrial protein synthesis; T cells abdominal aortic aneurysm (AAA); clonal expansion; doxycycline; drug target; matrix metalloproteinases; mitochondrial protein synthesis; T cells
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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. (CC BY 4.0).

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MDPI and ACS Style

Kroon, A.M.; Taanman, J.-W. Clonal Expansion of T Cells in Abdominal Aortic Aneurysm: A Role for Doxycycline as Drug of Choice? Int. J. Mol. Sci. 2015, 16, 11178-11195.

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