Gap junction reduction in cardiomyocytes following transforming growth factor-β treatment and Trypanosoma cruzi infection

• Main Authors: Mariana C Waghabi, Robson Coutinho-Silva, Jean-Jacques Feige, Maria de Lourdes Higuchi, David Becker, Geoffrey Burnstock, Tânia C de Araújo-Jorge
• Format: Article
• Language: English
• Published: Instituto Oswaldo Cruz, Ministério da Saúde 2009-12-01
• Series: Memórias do Instituto Oswaldo Cruz.
• Subjects: gap junction; heart; Chagas disease; transforming growth factor- β connexin 43
• Online Access: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762009000800004
• ISSN: 0074-0276; 1678-8060

Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-β (TGF-β). 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-β T. cruzi, or SB-431542, an inhibitor of TGF-β receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-β signalling had been shown previously to be highly activated. We demonstrated that TGF-β 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-β 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-β 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.