Gap junction reduction in cardiomyocytes following transforming growth factor-beta treatment and Trypanosoma cruzi infection.
Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-beta (TGF-beta). This cytokine increases during Trypanosoma cruzi infection, modulating fibrosis and the parasite cell cycle. We studied Cx43 expression in cardiomyocytes exposed or not to TGF-beta T. cruzi, or SB-431542, an inhibitor of TGF-beta receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-beta signalling had been shown previously to be highly activated. We demonstrated that TGF-beta treatment induced disorganised gap junctions in non-infected cardiomyocytes, leading to a punctate, diffuse and non-uniform Cx43 staining. A similar pattern was detected in T. cruzi-infected cardiomyocytes concomitant with high TGF-beta secretion. Both results were reversed if the cells were incubated with SB-431542. Similar tests were performed using human chronic chagasic patients and we confirmed a down-regulation of Cx43 expression, an altered distribution of plaques in the heart and a significant reduction in the number and length of Cx43 plaques, which correlated negatively with cardiomegaly. We conclude that elevated TGF-beta levels during T. cruzi infection promote heart fibrosis and disorganise gap junctions, possibly contributing to abnormal impulse conduction and arrhythmia that characterise severe cardiopathy in Chagas disease.
Laboratório de Inovações Terapêuticas, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, RJ, Brasil.
Mariana C
MC
Waghabi
Robson
R
Coutinho-Silva
Jean-Jacques
JJ
Feige
Maria de Lourdes
Mde L
Higuchi
David
D
Becker
Geoffrey
G
Burnstock
Tânia C de
TC
Araújo-Jorge
D000328:Adult; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D014355:Chagas Disease / Q000188:drug therapy / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism*; D004149:Dioxoles / Q000627:therapeutic use*; D005260:Female; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000627:therapeutic use*
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D018031:Connexin 43; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta