Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and

Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. whether enhancing the activity of sirtuin 1 (SIRT1) would be beneficial in maintaining heart health in Chagas disease. SIRT1 senses the redox shifts and integrates mitochondrial metabolism and inflammation. We found that treatment with SIRT1 agonists given in a therapeutic window of time after infection had no beneficial effects in reducing the cardiac remodeling and mitochondrial biogenic defects in chagasic mice. SIRT1 agonist however controlled the NFκB signaling of oxidative and inflammatory responses and helped preserve the left ventricular function in chagasic mice. 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. Introduction (or are also present in the southern US [4] Tonabersat and CDC estimates that >300 0 infected individuals are living in the US [5 Tonabersat 6 Currently only two drugs are available for Tonabersat the treatment of infection: nifurtimox and benznidazole. These drugs are curative in early infection phase but exhibit high toxicity and limited-to-no efficacy against chronic infection [7]. Thus there is a need for new drugs for the treatment of chronic Chagas disease. Mitochondria are the prime source of TIE1 energy providing ATP through oxidative phosphorylation (OXPHOS) pathway. A high copy number of mitochondrial DNA (mtDNA) reported to be ~6500 copies per diploid genome in myocardium [8] as well as the integrity of each mtDNA molecule is required to meet the high energy demand Tonabersat of the heart [9]. The mtDNA encodes 13 proteins that are essential for the normal assembly and function of the respiratory chain complexes. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) can be a member from the PGC category of transcription coactivators. PGC1α takes on an important part in the manifestation of nuclear DNA and mtDNA encoded genes that travel mitochondrial biogenesis and raise the oxidative phosphorylation (OXPHOS) capability [10]. Lately we demonstrated the mitochondrial respiratory string activity and oxidative phosphorylation capability were jeopardized in the myocardium of chronically contaminated rodents [11]. Further mtDNA content material and mtDNA encoded gene manifestation were reduced in leads to extreme inflammatory activation of macrophages and Compact disc8+T lymphocytes followed by increased manifestation of inflammatory mediators such as for example cytokines chemokines and nitric oxide synthase (NOS) in the center (evaluated in [13 14 Further reactive air varieties (ROS) are made by neutrophils and macrophages triggered by disease [14]. Besides infiltration of inflammatory infiltrate cardiomyocytes will also be reported to create cytokines and mitochondrial ROS in response to disease [15 16 The ROS induced adducts of DNA proteins and lipids had been exacerbated in the myocardium of chronically contaminated rodents and human patients [12 17 NFκB transcriptional factor signals oxidative and inflammatory responses [18] though mechanistic role of NFκB in chronic oxidative and inflammatory stress during CCM is yet to be elucidated. Sirtuin 1 (SIRT1) is a highly conserved member of the family of NAD+-dependent Sir2 histone deacetylases which deacetylates PGC1α at multiple lysine sites consequently increasing PGC1α activity [19]. SIRT1 has also been reported to sense the redox shifts and integrate mitochondrial metabolism and inflammation through post-transcriptional regulation of the transcription factors and histones [20]. Several small molecule agonists of SIRT1 have been reported in literature. For example resveratrol (3 5 4 a polyphenol found in red grape skins and red wine is a natural agonist of SIRT1 and has been shown to increase mitochondrial number and the expression of genes for oxidative phosphorylation [21]. SRT1720 is a selective small molecule activator of SIRT1 and it is 1 0 more potent than resveratrol [22]. SRT1720 has been Tonabersat demonstrated to improve mitochondrial oxidative metabolism [23] and attenuate aging-related cardiac myocyte dysfunction [24]. In this study we aimed to determine whether treatment with SIRT1 agonists will be beneficial in improving the heart function in Chagas disease. C57BL/6 mice were infected with infection and CCM. Results We first determined if enhancing the SIRT1 activity would.