title: SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells.
abstract: BACKGROUND
  The search for compounds able to counteract chemotherapy-induced heart failure is extremely important at the age of global cancer epidemic. The role of SIRT1 in the maintenance of progenitor cell homeostasis may contribute to its cardioprotective effects. SIRT1 activators, by preserving progenitor cells, could have a clinical relevance for the prevention of doxorubicin (DOXO)-cardiotoxicity.
  
  
  METHODS
  To determine whether SIRT1 activator, resveratrol (RES), interferes with adverse effects of DOXO on cardiac progenitor cells (CPCs): 1) human CPCs (hCPCs) were exposed in vitro to DOXO or DOXO+RES and their regenerative potential was tested in vivo in an animal model of DOXO-induced heart failure; 2) the in vivo effects of DOXO+RES co-treatment on CPCs were studied in a rat model.
  
  
  RESULTS
  In contrast to healthy cells, DOXO-exposed hCPCs were ineffective in a model of anthracycline cardiomyopathy. The in vitro activation of SIRT1 decreased p53 acetylation, overcame suppression of the IGF-1/Akt pro-survival and anti-apoptotic signaling, enhanced oxidative stress defense and prevented senescence and growth arrest of hCPCs. Priming with RES counterbalanced the onset of dysfunctional phenotype in DOXO-exposed hCPCs, partly restoring their ability to repair the damage with improvement in cardiac function and animal survival. The in vivo co-treatment DOXO+RES prevented the anthracycline-induced alterations in CPCs, partly preserving cardiac function.
  
  
  CONCLUSIONS
  SIRT1 activation protects DOXO-exposed CPCs and re-establishes their proper function. Pharmacological intervention at the level of tissue-specific progenitor cells may provide cardiac benefits for the growing population of long-term cancer survivors that are at risk of chemotherapy-induced cardiovascular toxicity.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy. Electronic address: antonella.deangelis@unina2.it.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piegari
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Loreta Pia
authors.initials: LP
authors.lastname: Ciuffreda
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Fiorella Angelica Valeria
authors.initials: FA
authors.lastname: Ferraiolo
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, Parma, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Frati
authors.affiliation: Immunohematology and Transfusional Medicine Unit, University-Hospital of Parma, Via Gramsci 14, Parma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fagnoni
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Liberato
authors.initials: L
authors.lastname: Berrino
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, Parma, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D032383:Myocytes, Cardiac / Q000187:drug effects; D016011:Normal Distribution; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; D004317:Doxorubicin; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Doxorubicin-induced cardiomyopathy; Human cardiac progenitor cells; Resveratrol; SIRT1