Myeloperoxidase is a potential molecular imaging and therapeutic target for the identification and stabilization of high-risk atherosclerotic plaque
Autor: | Jihan Talib, Imran Rashid, Minqin Ren, Ghassan J. Maghzal, Ana Maluenda, Yung-Chih Chen, Eva-Lotte Lindstedt, Saumitra K. Vajandar, David Cheng, Carl Power, Karlheinz Peter, Antony J Kettle, Roland Stocker, Erik Michaëlsson, Darren Newington, Andre Bongers, Andrew Jabbour, Amy Kate Searle |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Apolipoprotein E Pathology medicine.medical_specialty biology business.industry animal diseases Fibrous cap 030204 cardiovascular system & hematology medicine.disease Fibrin Coronary artery disease Lesion 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Atheroma In vivo Myeloperoxidase biology.protein Medicine medicine.symptom Cardiology and Cardiovascular Medicine business |
Zdroj: | European Heart Journal. 39:3301-3310 |
ISSN: | 1522-9645 0195-668X |
Popis: | Aims As the inflammatory enzyme myeloperoxidase (MPO) is abundant in ruptured human atherosclerotic plaques, we aimed to investigate the role of MPO as a potential diagnostic and therapeutic target for high-risk plaque. Methods and results We employed the tandem stenosis model of atherosclerotic plaque instability in apolipoprotein E gene knockout (Apoe-/-) mice. To test the role of MPO, we used Mpo-/-Apoe-/- mice and the 2-thioxanthine MPO inhibitor AZM198. In vivo MPO activity was assessed by liquid chromatography-tandem mass spectrometry detection of 2-chloroethidium generation from hydroethidine and by bis-5HT-DTPA-Gd (MPO-Gd) molecular magnetic resonance imaging (MRI), while plaque phenotype was verified histologically. Myeloperoxidase activity was two-fold greater in plaque with unstable compared with stable phenotype. Genetic deletion of MPO significantly increased fibrous cap thickness, and decreased plaque fibrin and haemosiderin content in plaque with unstable phenotype. AZM198 inhibited MPO activity and it also increased fibrous cap thickness and decreased fibrin and haemosiderin in plaque with unstable phenotype, without affecting lesion monocytes and red blood cell markers or circulating leukocytes and lipids. MPO-Gd MRI demonstrated sustained enhancement of plaque with unstable phenotype on T1-weighted imaging that was two-fold greater than stable plaque and was significantly attenuated by both AZM198 treatment and deletion of the Mpo gene. Conclusion Our data implicate MPO in atherosclerotic plaque instability and suggest that non-invasive imaging and pharmacological inhibition of plaque MPO activity hold promise for clinical translation in the management of high-risk coronary artery disease. |
Databáze: | OpenAIRE |
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