title: Activation of transcription factors AP-1 and NF-kappa B in murine Chagasic myocarditis.
abstract: The myocardium of CD1 mice was examined for the activation of signal transduction pathways leading to cardiac inflammation and subsequent remodeling during Trypanosoma cruzi infection (Brazil strain). The activity of three pathways of the mitogen-activated protein kinases (MAPKs) was determined. Immunoblotting revealed a persistent elevation of phosphorylated (activated) extracellular-signal-regulated kinase (ERK), which regulates cell proliferation. During infection there was a transient activation of p38 MAPK but no activation of Jun N-terminal kinase. Early targets of activated ERK, c-Jun and c-Fos, were elevated during infection, as demonstrated by semiquantitative reverse transcription-PCR. Immunostaining revealed that the endothelium and the interstitial cells were most intensely stained with antibodies to c-Jun and c-Fos. Soon after infection, AP-1 and NF-kappa B DNA binding activity was increased. Protein levels of cyclin D1, the downstream target of ERK and NF-kappa B, were induced during acute infection. Immunostaining demonstrated increased expression of cyclin D1 in the vascular and endocardial endothelium, inflammatory cells, and the interstitial areas. Increased expression of the cyclin D1-specific phosphorylated retinoblastoma protein (Ser780) was also evident. Immunoblotting and immunostaining also demonstrated increased expression of proliferating cellular nuclear antigen that was predominantly present in the inflammatory cells, interstitial areas (i.e., fibroblasts), and endothelium. These data demonstrate that T. cruzi infection results in activation of the ERK-AP-1 pathway and NF-kappa B. Cyclin D1 expression was also increased. These observations provide a molecular basis for the activation of pathways involved in cardiac remodeling in chagasic cardiomyopathy.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Huang
authors.forename: Stefka B
authors.initials: SB
authors.lastname: Petkova
authors.forename: Alex W
authors.initials: AW
authors.lastname: Cohen
authors.forename: Boumediene
authors.initials: B
authors.lastname: Bouzahzah
authors.forename: John
authors.initials: J
authors.lastname: Chan
authors.forename: Jian-nian
authors.initials: JN
authors.lastname: Zhou
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Factor
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiss
authors.forename: Mohan
authors.initials: M
authors.lastname: Krishnamachary
authors.forename: Shankar
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Murray
authors.initials: M
authors.lastname: Wittner
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
mesh_terms: D000818:Animals; D002598:Chagas Cardiomyopathy / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000032:analysis; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis / Q000235:genetics; D016160:Retinoblastoma Protein / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D016755:Proto-Oncogene Proteins c-jun; D016160:Retinoblastoma Protein; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases