Role of FAK signaling in chagasic cardiac hypertrophy

Tucci, Amanda Resende; Oliveira, Francisco Odencio Rodrigues de; Lechuga, Guilherme Curty; Oliveira, Gabriel Melo de; Eleuterio, Ana Carolina; Mesquita, Liliane Batista de; Farani, Priscila Silva Grijó; Britto, Constança; Moreira, Otacílio C.; Pereira, Mirian Cláudia de Souza

doi:10.1016/j.bjid.2020.08.007

Cited by 12 publications

(9 citation statements)

References 50 publications

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“…cruzi had not been studied. Herein, AT-RvD1 was shown to reduce both the cross-sectional area of cardiomyocytes and the transcription of hypertrophy markers such as ANP and BNP, which have been associated with different stages and severity of CCC [ 63 , 64 ]. Furthermore, during T .…”

Section: Discussionmentioning

confidence: 99%

“…To the best of our knowledge, until now, the effect of AT-RvD1 on hypertrophy produced by infection with T. cruzi had not been studied. Herein, AT-RvD1 was shown to reduce both the cross-sectional area of cardiomyocytes and the transcription of hypertrophy markers such as ANP and BNP, which have been associated with different stages and severity of CCC [63,64]. Furthermore, during T. cruzi infection, the participation of endothelin-1, cardiotrophin-1, and cytokines such as TNFα and IL-1β has been previously highlighted as pro-hypertrophic [65].…”

Section: At-rvd1 Decreases the Inflammatory Process In Early Chronic CDmentioning

confidence: 91%

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Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease

et al. 2021

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Background Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. In 30% of cases, after years of infection and in the absence of treatment, the disease progresses from an acute asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapeutic agent to regulate the pro-inflammatory state during the early chronic phase of Chagas disease. Methodology/Principal findings C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 μg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 μg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the early chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue. Conclusions/Significance AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during early chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

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Section: Discussionmentioning

confidence: 99%

Section: At-rvd1 Decreases the Inflammatory Process In Early Chronic CDmentioning

confidence: 91%

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease

et al. 2021

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“…Increased cytosolic Ca 2+ has been shown to trigger local disassembly of FAs in human U87 astrocytoma cells through the phosphorylation of FAK at Tyr 397 [37]. Furthermore, FAK activation has been shown to cause cardiomyopathies [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Filamin C Deficiency Impairs Sarcomere Stability and Activates Focal Adhesion Kinase through PDGFRA Signaling in Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Gao,

He,

Lam

et al. 2024

Cells

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Truncating mutations in filamin C (FLNC) are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein and is known to interact with transmembrane and structural proteins; hence, the ablation of FLNC in cardiomyocytes is expected to dysregulate cell adhesion, cytoskeletal organization, sarcomere structural integrity, and likely nuclear function. Our previous study showed that the transcriptional profiles of FLNC homozygous deletions in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are highly comparable to the transcriptome profiles of hiPSC-CMs from patients with FLNC truncating mutations. Therefore, in this study, we used CRISPR-Cas-engineered hiPSC-derived FLNC knockout cardiac myocytes as a model of FLNC cardiomyopathy to determine pathogenic mechanisms and to examine structural changes caused by FLNC deficiency. RNA sequencing data indicated the significant upregulation of focal adhesion signaling and the dysregulation of thin filament genes in FLNC-knockout (FLNCKO) hiPSC-CMs compared to isogenic hiPSC-CMs. Furthermore, our findings suggest that the complete loss of FLNC in cardiomyocytes led to cytoskeletal defects and the activation of focal adhesion kinase. Pharmacological inhibition of PDGFRA signaling using crenolanib (an FDA-approved drug) reduced focal adhesion kinase activation and partially normalized the focal adhesion signaling pathway. The findings from this study suggest the opportunity in repurposing FDA-approved drug as a therapeutic strategy to treat FLNC cardiomyopathy.

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“…To the best of our knowledge, until now, the effect of AT-RvD1 on hypertrophy produced by infection with T. cruzi had not been studied. Herein, AT-RvD1 was shown to reduce both the crosssectional area of cardiomyocytes and the transcription of hypertrophy markers such as ANP and BNP, which have been associated with different stages and severity of CCC [54,55]. Furthermore, during T. cruzi infection, the participation of endothelin-1, cardiotrophin-1, and cytokines such as TNFα and IL-1β has been previously highlighted as pro-hypertrophic [56].…”

Section: At-rvd1 Decreases the Inflammatory Process In Chronic CDmentioning

confidence: 91%

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation through N-formyl peptide receptor 2 in a chronic murine model of Chagas disease

Carrillo

Rabelo

Barbosa

et al. 2021

Preprint

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Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. After years of infection and in the absence of treatment, the disease progresses from an acute and asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapy aid to regulate the pro-inflammatory state during the chronic phase of Chagas disease. C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 μg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 μg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in the immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue. Thus, AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

show abstract

Role of FAK signaling in chagasic cardiac hypertrophy

Cited by 12 publications

References 50 publications

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease

Filamin C Deficiency Impairs Sarcomere Stability and Activates Focal Adhesion Kinase through PDGFRA Signaling in Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation through N-formyl peptide receptor 2 in a chronic murine model of Chagas disease

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