Trypanosoma cruzi down-regulates mechanosensitive proteins in cardiomyocytes

Abstract

BACKGROUND Cardiac physiology depends on coupling and electrical and mechanical coordination through the intercalated disc. Focal adhesions offer mechanical support and signal transduction events during heart contraction-relaxation processes. Talin links integrins to the actin cytoskeleton and serves as a scaffold for the recruitment of other proteins, such as paxillin in focal adhesion formation and regulation. Chagasic cardiomyopathy is caused by infection by Trypanosoma cruzi and is a debilitating condition comprising extensive fibrosis, inflammation, cardiac hypertrophy and electrical alterations that culminate in heart failure. OBJECTIVES Since mechanotransduction coordinates heart function, we evaluated the underlying mechanism implicated in the mechanical changes, focusing especially in mechanosensitive proteins and related signalling pathways during infection of cardiac cells by T. cruzi . METHODS We investigated the effect of T. cruzi infection on the expression and distribution of talin/paxillin and associated proteins in mouse cardiomyocytes in vitro by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR). FINDINGS Talin and paxillin spatial distribution in T. cruzi- infected cardiomyocytes in vitro were altered associated with a downregulation of these proteins and mRNAs levels at 72 h post-infection (hpi). Additionally, we observed an increase in the activation of the focal adhesion kinase (FAK) concomitant with increase in β-1-integrin at 24 hpi. Finally, we detected a decrease in the activation of FAK at 72 hpi in T. cruzi -infected cultures. MAIN CONCLUSION The results suggest that these changes may contribute to the mechanotransduction disturbance evidenced in chagasic cardiomyopathy.

Role of FAK signaling in chagasic cardiac hypertrophy

“…Interestingly, an in vitro model of acute infection by T. cruzi with high parasitic load revealed loss of spatial organization and downregulation of mechanosensitive proteins in cardiomyocytes, such as talin and paxilin, inducing a downregulation of the FAK signaling pathway activation and therefore, suggesting a disruption of integrin-dependent signaling transduction. 41 FAK signaling activation has also been shown to be a beneficial event in ischemia/reperfusion, promoting cardiomyocytes survival under stress conditions. Activation of the NF-kB survival signaling pathway, as downstream of FAK activation, modulates FAK-dependent cardioprotection by reducing pro-apoptotic genes level.…”

Comparative microRNA profiling of Trypanosoma cruzi infected human cells

“…We previously showed that infected cardiomyocytes present extensive transcriptomic changes at earlier time points of infection ( Libisch et al., 2018 ). Other authors also described cardiomyocyte changes at the RNA -and also structural- level after 48 and 72 h post interaction ( Pereira et al., 2005 ; Manque et al., 2011 ; Melo et al., 2019 ). The minimal number of miRNAs modulated by T. cruzi infection in cardiomyocytes at 24 hpi ( i.e.…”

Benznidazole and amiodarone combined treatment attenuates cytoskeletal damage in Trypanosoma cruzi-infected cardiac cells

“…We also investigated the impact of the combined treatment on the cytoarchitectural recovery of infected HCs. It has been widely reported that in HCs, T. cruzi (Y strain) infection induces a decrease in the expression and structural disorganization of cytoskeleton proteins, such as F-actin, α-actinin, vinculin, talin and paxillin, after 72 hpi ( Melo et al., 2004 ; Melo et al., 2006 ; Melo et al., 2019 ). Furthermore, the microfilament destruction caused by the infection is one of the major factors contributing to cardiac arrhythmias due to the loss of transmission of the contractility force between cardiomyocytes ( Pereira et al., 1993 ; Silva et al., 2006 ; Adesse et al., 2011 ).…”