title: SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy.
abstract: BACKGROUND
  Doxorubicin (DOXO) is an effective anti-neoplastic drug but its clinical benefits are hampered by cardiotoxicity. Oxidative stress, apoptosis and myocardial fibrosis mediate the anthracycline cardiomyopathy. ROS trigger TGF-β pathway that activates cardiac fibroblasts promoting fibrosis. Myocardial stiffness contributes to diastolic dysfunction, less studied aspect of anthracycline cardiomyopathy. Considering the role of SIRT1 in the inhibition of the TGF-β/SMAD3 pathway, resveratrol (RES), a SIRT1 activator, might improve cardiac function by interfering with the development of cardiac fibrosis in a model of DOXO-induced cardiomyopathy.
  
  
  METHODS
  F344 rats received a cumulative dose of 15 mg/kg of DOXO in 2 weeks or DOXO+RES (DOXO and RES, 2.5mg/kg/day, concomitantly for 2 weeks and then RES alone for 1 more week). The effects of RES on cardiac fibroblasts were also tested in vitro.
  
  
  RESULTS
  Along with systolic dysfunction, DOXO was also responsible of diastolic abnormalities. Myocardial stiffness correlated with fibroblast activation and collagen deposition. DOXO+RES co-treatment significantly improved ± dP/dt and, more interestingly, ameliorated end-diastolic pressure/volume relationship. Treatment with RES resulted in reduced fibrosis and fibroblast activation and, most importantly, the mortality rate was significantly reduced in DOXO+RES group. Fibroblasts isolated from DOXO+RES-treated rats, in which SIRT1 was upregulated, showed decreased levels of TGF-β and pSMAD3/SMAD3 when compared to cells isolated from DOXO-exposed hearts.
  
  
  CONCLUSIONS
  Our findings reveal a key role of SIRT1 in supporting animal survival and functional parameters of the heart. SIRT1 activation by interfering with fibrogenesis can improve relaxation properties of myocardium and attenuate myocardial remodeling related to chemotherapy.
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: 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: 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: 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: 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: Alessia
authors.initials: A
authors.lastname: Rivellino
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 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. 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: Konrad
authors.initials: K
authors.lastname: Urbanek
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D002478:Cells, Cultured; D003971:Diastole / Q000187:drug effects*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D005355:Fibrosis; D051381:Rats; D011916:Rats, Inbred F344; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D013267:Stilbenes; D004317:Doxorubicin; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Cardiac fibroblasts; Diastolic dysfunction; Doxorubicin-induced cardiomyopathy; Resveratrol; SIRT1