title: Glycosylphosphatidylinositol-induced cardiac myocyte death might contribute to the fatal outcome of Plasmodium falciparum malaria.
abstract: BACKGROUND
  Glycosylphosphatidylinositol (GPI) purified from Plasmodium falciparum has been shown to play an important role as a toxin in the pathology of malaria. Previous studies demonstrated cardiac involvement in patients suffering from severe malaria due to P. falciparum. Therefore, we tested the hypothesis that GPI induces apoptosis in cardiomyocytes.
  
  
  RESULTS
  By using TUNEL and caspase activity assays, we provided evidence for apoptosis induction in cardiomyocytes by P. falciparum GPI after 48 h of incubation. A similar result was obtained in heart cells of mice 48 h after in vivo injection of GPI. Gene expression analyses in GPI-treated cardiomyocytes showed an up-regulation of apoptotic genes (apaf-1, bax) and of a myocardial damage marker bnp (brain natriuretic peptide), while a down-regulation was observed for the anti-apoptotic gene bcl-2 and for the heat shock protein hsp70. In spite of inflammatory cytokine gene up-regulation by GPI, co-culture with peripheral mononuclear cells (PMNCs) did not change the results obtained with cardiomyocytes alone, indicating a direct effect of GPI on cardiac myocytes. Co-culture with non-myocytic cardiac cells (NMCCs) resulted in up-regulation of Hsp70 and Bcl-2 genes in GPI-treated cardiomyocytes but without repercussion on the apoptosis level. A malaria-infected patient, presenting fulminant heart failure showed typical signs of cardiac myocyte apoptosis demonstrating the clinical relevance of toxin induced heart damage for the lethality of malaria. Our studies performed in vitro and in mice suggest that the GPI could be responsible for cardiomyocyte apoptosis that occurred in this patient.
  
  
  CONCLUSIONS
  Plasmodium falciparum GPI-induced apoptosis might participate in the lethality of malaria.
authors.affiliation: Department of Internal Medicine - Cardiology, Philipps-University of Marburg, University Hospital, Baldingerstrasse 1, 35043 Marburg/Lahn, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Wennicke
authors.forename: Françoise
authors.initials: F
authors.lastname: Debierre-Grockiego
authors.forename: Dominic
authors.initials: D
authors.lastname: Wichmann
authors.forename: Norbert W
authors.initials: NW
authors.lastname: Brattig
authors.forename: Sabine
authors.initials: S
authors.lastname: Pankuweit
authors.forename: Bernhard
authors.initials: B
authors.lastname: Maisch
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schwarz
authors.forename: Volker
authors.initials: V
authors.lastname: Ruppert
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D019254:Genes, bcl-2; D017261:Glycosylphosphatidylinositols / Q000378:metabolism* / Q000633:toxicity; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology*; D010963:Plasmodium falciparum / Q000378:metabolism* / Q000472:pathogenicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D053477:Apoptotic Protease-Activating Factor 1; D017931:DNA Primers; D017261:Glycosylphosphatidylinositols; D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein