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.
Waghabi
Mariana C
MC
Laboratório de Inovações Terapêuticas, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, RJ, Brasil.
Coutinho-Silva
Robson
R
Feige
Jean-Jacques
JJ
Higuchi
Maria de Lourdes
Mde L
Becker
David
D
Burnstock
Geoffrey
G
Araújo-Jorge
Tânia C de
TC
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