title: 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.
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 (resveratrol or SRT1720), and monitored during chronic phase (~150 days post-infection). Resveratrol treatment was partially beneficial in controlling the pathologic processes in Chagas disease. The 3-weeks SRT1720 therapy provided significant benefits in restoring the left ventricular (LV) function (stroke volume, cardiac output, ejection fraction etc.) in chagasic mice, though cardiac hypertrophy presented by increased thickness of the interventricular septum and LV posterior wall, increased LV mass, and disproportionate synthesis of collagens was not controlled. SRT1720 treatment preserved the myocardial SIRT1 activity and PGC1α deacetylation (active-form) that were decreased by 53% and 9-fold respectively, in chagasic mice. Yet, SIRT1/PGC1α-dependent mitochondrial biogenesis (i.e., mitochondrial DNA content, and expression of subunits of the respiratory complexes and mtDNA replication machinery) was not improved in chronically-infected/SRT1720-treated mice. Instead, SRT1720 therapy resulted in 2-10-fold inhibition of Tc-induced oxidative (H2O2 and advanced oxidation protein products), nitrosative (inducible nitric oxide synthase, 4-hydroxynonenal, 3-nitrotyrosine), and inflammatory (IFNγ, IL1β, IL6 and TNFα) stress and inflammatory infiltrate in chagasic myocardium. These benefits were delivered through SIRT1-dependent inhibition of NFκB transcriptional activity. We conclude that Tc inhibition of SIRT1/PGC1α activity was not a key mechanism in mitochondrial biogenesis defects during Chagas disease. SRT1720-dependent SIRT1 activation led to suppression of NFκB transcriptional activity, and subsequently, oxidative/nitrosative and inflammatory pathology were subdued, and antioxidant status and LV function were enhanced in chronic chagasic cardiomyopathy.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas.
authors.forename: Xianxiu
authors.identifier: http://orcid.org/0000-0003-1415-0328
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wen
authors.affiliation: Department of Pathology, UTMB, Galveston, Texas.
authors.forename: Sue-Jie
authors.identifier: http://orcid.org/0000-0002-3305-9952
authors.initials: SJ
authors.lastname: Koo
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas.
authors.forename: Lisa Yi
authors.initials: LY
authors.lastname: Liang
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas.|Department of Pathology, UTMB, Galveston, Texas.|Institute for Human Infections and Immunity, UTMB, Galveston, Texas.
authors.forename: Nisha Jain
authors.identifier: http://orcid.org/0000-0002-3453-2369
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D002598:Chagas Cardiomyopathy / Q000378:metabolism*; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000187:drug effects / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D059467:Transcriptome; D014349:Trypanosoma cruzi
chemical_list: D000975:Antioxidants; D006576:Heterocyclic Compounds, 4 or More Rings; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C525422:SRT1720; D013267:Stilbenes; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol