SIRT1 ACTIVATION IMPROVES HEART FUNCTION THROUGH INHIBITION OF INFLAMMATION IN CHAGAS DISEASE

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Abstract

Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes and integrates mitochondrial metabolism and inflammation; and SIRT1 deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infected with Trypanosoma cruzi (Tc), treated with SIRT1 agonists (SRT1720), and monitored during chronic phase (~150 days post-infection). In this study, we determined whether enhancing the activity of sirtuin 1 (SIRT1) would be beneficial in maintaining heart health in Chagas disease. We found that treatment with SIRT1 agonists, given in a therapeutic window of time after Trypanosoma cruzi infection, had no beneficial effects in reducing the cardiac remodeling and mitochondrial biogenic defects in chagasic mice. SIRT1 agonist, however, controlled the NFB signaling of oxidative and inflammatory responses and helped preserve the left ventricular function in chagasic mice. We also found that SRT1720 decreased the proinflammatory differentiation of macrophages in spleen and heart tissue in chronic chagasic mice. SRT1720-treated chagasic mice also significantly reduced in proinflammatory cytokines’ mRNA level and protein level compared to splenic macrophages of chagasic mice. We concluded that co-delivery of SIRT1 agonists with other small molecules that inhibit mitochondrial dysfunction, cardiac fibrosis, and parasite persistence will potentially form a complete therapeutic regimen against Chagas disease.

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Chagas disease, inflammation, oxidative stress, SIRT1, macrophages
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