TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas’ heart disease

Abstract

TGF-β involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-β signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of TβR1/ALK5, on cardiac function in an experimental model of chronic Chagas’ heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (10 2 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-β signaling pathway reduced TGF-β/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3 + cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas’ heart disease by TGF-β inhibitors.

IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease

“…Moreover, we found that the reduced expression of pro-inflammatory cytokines and TGF-β was associated with heart function amelioration. Similarly, a reduction in serum TGF-β concentration through pharmacological treatment associated with heart function improvement has been observed by others ( 71 ).…”

CCL3/Macrophage Inflammatory Protein-1α Is Dually Involved in Parasite Persistence and Induction of a TNF- and IFNγ-Enriched Inflammatory Milieu in Trypanosoma cruzi-Induced Chronic Cardiomyopathy

“…We have previously shown that chronically Colombianinfected C57BL/6 mice show cardiomegaly, echocardiographic and electrical abnormalities that resembles those found in Chagas' heart disease (6,26,32,46). These features were associated with the intensity of myocarditis and levels of proinflammatory cytokines in the heart tissue (26,30).…”

Effect of Oral Losartan on Orthobiologics: Implications for Platelet-Rich Plasma and Bone Marrow Concentrate—A Rabbit Study

“…Interestingly, we did not observe significant differences between the losartan and control groups in LP-PRP or WB TGF-β1 concentrations. TGF-β1 is an essential Smad factor involved in downstream intracellular signaling and, more specifically, increasing ECM protein expression (i.e., matrix metalloproteinases [MMPs], tissue inhibitors of metalloproteinases [TIMPs]) [ 38 ]. The most notable role of TGF-β1 is stimulating fibrosis formation during connective tissue remodeling [ 39 ].…”

“…As a result, several anti-fibrotic medications have been developed to reduce local and systemic TGF-β1 levels by implicating the Smad2/3 pathway. Angiotensin-receptor blocker, losartan, has demonstrated its anti-fibrotic effects in cardiac [ 8 , 38 , 40 , 41 , 42 ] and skeletal muscle [ 12 , 13 , 14 , 15 , 19 ], as well as reducing systemic levels of TGF-β1 in transplant patients [ 43 , 44 ]. In the present study, there were no significant differences between TGF-β1 levels in the losartan and control groups; however, losartan dosing and timing in which the blood specimens were collected could have had an impact on TGF-β1 expression.…”