title: Trypanosoma brucei cathepsin-L increases arrhythmogenic sarcoplasmic reticulum-mediated calcium release in rat cardiomyocytes.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: College 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.
authors.forename: Elspeth B
authors.initials: EB
authors.lastname: Elliott
authors.forename: Douglas
authors.initials: D
authors.lastname: McCarroll
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.forename: Claire E
authors.initials: CE
authors.lastname: Welsh
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Panissidi
authors.forename: Nathaniel G
authors.initials: NG
authors.lastname: Jones
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Rossor
authors.forename: Andy
authors.initials: A
authors.lastname: Tait
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Morrison
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Loughrey
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: D011943:Receptors, Adrenergic, beta; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D056668:Cathepsin L; D002118:Calcium
keywords: Calcium; Cardiomyocyte; Sarcoplasmic reticulum; Trypanosome; Trypanosomiasis
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