title: Trypanosoma cruzi infection (Chagas' disease) of mice causes activation of the mitogen-activated protein kinase cascade and expression of endothelin-1 in the myocardium.
abstract: Chagas' disease, caused by the parasite Trypanosoma cruzi, is an important cause of heart disease. Previous studies from this laboratory revealed that microvascular spasm and myocardial ischemia were observed in infected mice. Infection of endothelial cells with this parasite increased the synthesis of biologically active endothelin-1 (ET-1). Therefore. in the myocardium of T. cruzi-infected mice, we examined ET-1 expression and the p42/44-mitogen activated protein kinase (MAPK)-AP-1 pathway that regulates the expression of ET-1. There was parasitism and myonecrosis in the myocardium of infected C57BL/6 mice. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed elevated mRNA expression of transcription factor AP-1 (c-jun and c-fos) and increased AP-1 DNA binding activity as determined by electrophoretic mobility shift assay (EMSA). Western blot analysis demonstrated an increase in the phosphorylated forms of extracellular signal-regulated kinase (ERK1/2). ET-1 mRNA was upregulated in the myocardium of infected mice. Immunohistochemical and immunoelectron microscopy using anti-ET-1 antibody detected increased expression in cardiac myocytes and endothelium of these mice. These data suggest that ET-1 contributes to chagasic cardiomyopathy and that the mechanism of the increased expression of ET-1 is a result of the activation of the MAPK pathway by T. cruzi infection.
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.forename: S B
authors.initials: SB
authors.lastname: Petkova
authors.forename: R G
authors.initials: RG
authors.lastname: Pestell
authors.forename: B
authors.initials: B
authors.lastname: Bouzahzah
authors.forename: J
authors.initials: J
authors.lastname: Chan
authors.forename: H
authors.initials: H
authors.lastname: Magazine
authors.forename: L M
authors.initials: LM
authors.lastname: Weiss
authors.forename: G J
authors.initials: GJ
authors.lastname: Christ
authors.forename: M P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: S A
authors.initials: SA
authors.lastname: Douglas
authors.forename: V
authors.initials: V
authors.lastname: Shtutin
authors.forename: S K
authors.initials: SK
authors.lastname: Halonen
authors.forename: M
authors.initials: M
authors.lastname: Wittner
authors.forename: H B
authors.initials: HB
authors.lastname: Tanowitz
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics*; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D020928:Mitogen-Activated Protein Kinases