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SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Signal Transduction and Targeted Therapy 2020年第1期5卷 2322-2331页

作者： Xavier Palomer MSilvia Román-Azcona Javier Pizarro-Delgado Ana Planavila Francesc Villarroya Brenda Valenzuela-Alcaraz Fátima Crispi Álvaro Sepúlveda-Martínez Irene Miguel-Escalada Jorge Ferrer JFrancisco Nistal Raquel García Mercy MDavidson emma barroso Manuel Vázquez-Carrera Department of Pharmacology Toxicology and Therapeutic ChemistryIBUB(Institut de Biomedicina de la Universitat de Barcelona)Research Institute-Pediatric Research InstituteHospital Sant Joan de Déuand CIBER de Diabetes y Enfermedades Metabólicas Asociadas(CIBERDEM)Faculty of Pharmacy and Food SciencesUniversity of BarcelonaBarcelonaSpain Department of Biochemistry and Molecular Biomedicine IBUB and CIBER Fisiopatología de la Obesidad y Nutrición(CIBEROBN)Faculty of BiologyUniversity of BarcelonaBarcelonaSpain aBCNatal-Barcelona Center for Maternal–Fetal and Neonatal Medicine(Hospital Clínic and Hospital Sant Joan de Deu) Institut d’Investigacions Biomèdiques August Pi i SunyerUniversitat de Barcelonaand Center for Biomedical Research on Rare Diseases(CIBER-ER)BarcelonaSpain Genomic Programming of Betacells Laboratory Institut d’Investigacions August Pi i Sunyer(IDIBAPS)and CIBERDEMBarcelonaSpain Section of Epigenomics and Disease Department of Medicineand National Institute for Health Research(NIHR)Imperial Biomedical Research CentreImperial College LondonLondonUK Servicio de Cirugía Cardiovascular Hospital Universitario Marqués de ValdecillaDepartamento de Ciencias Médicas y QuirúrgicasFacultad de MedicinaUniversidad de CantabriaInstituto de Investigación Marqués de Valdecilla(IDIVAL)Centro de Investigación Biomédica en Red Cardiovascular(CIBERCV)Instituto de Salud Carlos IIISantanderSpain Departamento de Fisiología y Farmacología Facultad de MedicinaUniversidad de CantabriaInstituto de Investigación Marqués de Valdecilla(IDIVAL)SantanderSpain Department of Radiation Oncology Columbia UniversityNew YorkNYUSA

Sirtuin 3(SIRT3)is a deacetylase that modulates proteins that control metabolism and protects against oxidative *** of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac *** this study,we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 ***3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of *** with this,SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α.Notably,these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of ***,we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its *** findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 *** fibrosis and inflammation are crucial in the progression of cardiac hypertrophy,heart failure,and diabetic cardiomyopathy,our results point to SIRT3 as a potential target for treating these diseases.

关键词： SIRT3 inflammation cardiac

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