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Trypanosoma brucei cathepsin-L increases arrhythmogenic sarcoplasmic reticulum-mediated calcium release in rat
Elspeth B Elliott1, Douglas McCarroll, Hisashi Hasumi
1College of Medical, Veterinary and Life Sciences, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow Cardiovascular Research Centre, University Place, Glasgow G12 8TA, UK.
Insights
African trypanosomes cause cardiac dysfunction by releasing cathepsin-L, which disrupts sarcoplasmic reticulum calcium handling in heart cells, independent of immune responses. This leads to arrhythmias and potential heart failure.
Area of Science:
- Cardiology
- Parasitology
- Molecular Biology
Background:
- African trypanosomiasis, caused by Trypanosoma brucei, leads to neurological and cardiac dysfunction.
- The cardiac pathogenesis of the disease is not well understood.
- Neurological aspects are well-studied, but cardiac effects require further investigation.
Purpose of the Study:
- To investigate whether Trypanosoma brucei can directly alter cardiac function.
- To determine if trypanosomes affect cardiac function independently of systemic immune responses.
- To elucidate the specific mechanisms by which trypanosomes impact heart cells.
Main Methods:
- Isolated adult rat ventricular cardiomyocytes and whole rat hearts were exposed to T. brucei and its culture media.
- Confocal imaging was used to analyze calcium (Ca2+) release.
- Inhibitors, recombinant proteins, RNAi, and specific peptides were employed to identify the causative agent and pathways.
Main Results:
- T. brucei and its supernatant increased the frequency of arrhythmogenic Ca2+ waves in cardiomyocytes.
- The parasite's cathepsin-L (TbCatL) was identified as the key mediator of these effects.
- TbCatL altered sarcoplasmic reticulum (SR) function by increasing SERCA activity, reducing SR Ca2+ content, and enhancing Ca2+ leak, involving CaMKII.
- Arrhythmic events were also observed in whole heart experiments.
Conclusions:
- African trypanosomes can directly impair cardiac function independently of systemic immunity.
- Extracellular TbCatL plays a crucial role in altering cardiac SR function and causing arrhythmias.
- This study reveals a novel mechanism of cardiac pathogenesis in African trypanosomiasis.
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 Ca(2+) release (Ca(2+) 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 Ca(2+) content, suggesting a concomitant increased SR-mediated Ca(2+) leak. This conclusion was supported by data demonstrating that TbCatL increased Ca(2+) 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.
