title: SIRT1 suppresses doxorubicin-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways.
abstract: BACKGROUND
  SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro.
  
  
  METHODS
  We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes.
  
  
  RESULTS
  SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes.
  
  
  CONCLUSIONS
  These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University and Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ruan
authors.forename: Chunlin
authors.initials: C
authors.lastname: Dong
authors.forename: Jigar
authors.initials: J
authors.lastname: Patel
authors.forename: Chao
authors.initials: C
authors.lastname: Duan
authors.forename: Xinyue
authors.initials: X
authors.lastname: Wang
authors.forename: Xi
authors.initials: X
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.forename: Lianmei
authors.initials: L
authors.lastname: Pu
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004317:Doxorubicin / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000235:genetics; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000096:biosynthesis*; D013267:Stilbenes / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis*
chemical_list: D013267:Stilbenes; D009536:Niacinamide; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol