SIRT1-PGC1α-NFκB Pathway of Oxidative and Inflammatory Stress during Trypanosoma cruzi Infection: Benefits of SIRT1-Targeted Therapy in Improving Heart Function in Chagas Disease

• DOI: 10.1371/journal.ppat.1005954
• Publication Date: 2016-10-20T17:55:54Z
• Authors: Xianxiu Wan; Jian-jun Wen; Sue-Jie Koo; Lisa Yi Liang; Nisha Jain Garg
• Keywords: Sirtuin 1; Chagas Disease; Bioenergetics

Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes integrates metabolism inflammation; deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infected with Trypanosoma cruzi (Tc), treated agonists (resveratrol or SRT1720), monitored during chronic phase (~150 days post-infection). Resveratrol treatment was partially beneficial controlling pathologic processes Chagas disease. The 3-weeks SRT1720 therapy provided significant benefits restoring left ventricular (LV) function (stroke volume, cardiac output, ejection fraction etc.) mice, though hypertrophy thickness of interventricular septum LV posterior wall, mass, disproportionate synthesis collagens not controlled. preserved myocardial activity PGC1α deacetylation (active-form) that 53% 9-fold respectively, mice. Yet, SIRT1/PGC1α-dependent biogenesis (i.e., DNA content, expression subunits respiratory complexes mtDNA replication machinery) improved chronically-infected/SRT1720-treated Instead, resulted 2-10-fold inhibition Tc-induced oxidative (H2O2 advanced oxidation protein products), nitrosative (inducible nitric oxide synthase, 4-hydroxynonenal, 3-nitrotyrosine), inflammatory (IFNγ, IL1β, IL6 TNFα) infiltrate myocardium. These delivered through SIRT1-dependent NFκB transcriptional activity. We conclude Tc SIRT1/PGC1α key mechanism defects SRT1720-dependent activation led to suppression activity, subsequently, oxidative/nitrosative pathology subdued, antioxidant status enhanced cardiomyopathy.