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Lookup NU author(s): Dr Claire WelshORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Aims: African trypanosomiasis, caused by Trypanosoma brucei species, leads to both neurological and cardiac dysfunction and can be fatal if untreated. While the neurological-related pathogenesis is well studied, the cardiac pathogenesis remains unknown. The current study exposed isolated ventricular cardiomyocytes and adult rat hearts to T. brucei to test whether trypanosomes can alter cardiac function independent of a systemic inflammatory/immune response. Methods and results: Using confocal imaging, T. brucei and T. brucei culture media (supernatant) caused an increased frequency of arrhythmogenic spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca2+ release (Ca2+ waves) in isolated adult rat ventricular cardiomyocytes. Studies utilising inhibitors, recombinant protein and RNAi all demonstrated that this altered SR function was due to T. brucei cathepsin-L (TbCatL). Separate experiments revealed that TbCatL induced a 10-15% increase of SERCA activity but reduced SR Ca2+ content, suggesting a concomitant increased SR-mediated Ca2+ leak. This conclusion was supported by data demonstrating that TbCatL increased Ca2+ wave frequency. These effects were abolished by autocamtide-2-related inhibitory peptide, highlighting a role for CaMKII in the TbCatL action on SR function. Isolated Langendorff perfused whole heart experiments confirmed that supernatant caused an increased number of arrhythmic events. Conclusion: These data demonstrate for the first time that African trypanosomes alter cardiac function independent of a systemic immune response, via a mechanism involving extracellular cathepsin-L-mediated changes in SR function. © 2013 Published by Oxford University Press on behalf of the European Society of Cardiology.
Author(s): Elliott EB, McCarroll D, Hasumi H, Welsh CE, Panissidi AA, Jones NG, Rossor CL, Tait A, Smith GL, Mottram JC, Morrison LJ, Loughrey CM
Publication type: Article
Publication status: Published
Journal: Cardiovascular Research
Year: 2013
Volume: 100
Issue: 2
Pages: 325-335
Print publication date: 01/11/2013
Online publication date: 26/07/2013
Date deposited: 17/10/2019
ISSN (print): 0008-6363
ISSN (electronic): 1755-3245
Publisher: Oxford University Press
URL: https://doi.org/10.1093/cvr/cvt187
DOI: 10.1093/cvr/cvt187
PubMed id: 23892734
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