Abstract 201: Enhancing Pgc-1α Activity Improves Heart Function Through Activating Mitochondrial Biogenesis in Chagas Disease

Abstract

Chronic chagasic cardiomyopathy (CCM) is presented with ventricular hypertrophy and contractile dysfunction that can lead to heart failure. I have found that a substantial decline in mitochondrial biogenesis and SIRT1/PGC-1α activity ensue in chronic chagasic mice. It was evidenced by the decline in mitochondrial DNA content as well as mRNA levels of mitochondrial encoded genes and mtDNA replication machinery. Further, the activity of SIRT1 (required for PGC-1α activation) was decreased and associated with decreased nuclear levels of PGC-1-regulated NRF1 transcription factor in chagasic hearts. The mitochondrial size and number were also reduced in chagasic heart, determined by electron microscopy. Therefore, we hypothesized that enhancing the SIRT1/PGC-1α activity by SIRT1 agonist would improve heart function through activating mitochondrial biogenesis in Chagasic disease. Mice were infected with T. cruzi, and beginning at day 90 post-infection (pi), treated with resveratrol (SIRT1 agonist) or metformin (AMPK agonist, can enhance SIRT1 activity) for 21 days; and then heart function was monitored at 150 days pi. We found that treatment with resveratrol partially attenuated the heart dysfunction (stroke volume, cardiac output, ejection fraction, heart rate) and cardiac hypertrophy in chagasic mice. These benefits were associated with improved expression of the mitochondrial DNA encoded genes and mtDNA content though the expression of genes involved in mtDNA replication was not improved. Treatment with metformin was not significantly beneficial in improving the CCM outcomes. The partial beneficial effects of resveratrol could be due to inefficient activation of SIRT1 or delayed start of the treatment. We plan to treat mice with SIRT1 agonist SIRT1720 (10 fold more active than resveratrol) during the indeterminate phase of T. cruzi infection in next set of experiments. This study will improve our understanding of the molecular and immune mechanisms of chagasic heart disease and will provide a novel treatment for chronically-infected chagasic patients.