title: Survivin gene therapy attenuates left ventricular systolic dysfunction in doxorubicin cardiomyopathy by reducing apoptosis and fibrosis.
abstract: OBJECTIVE
  The aim of this study was to investigate anti-apoptotic gene therapy using ultrasound-mediated plasmid delivery of survivin, an inhibitor of apoptosis protein, to prevent apoptosis and to attenuate left ventricular (LV) systolic dysfunction in a model of heart failure induced by doxorubicin.
  
  
  RESULTS
  Effect of survivin transduction was investigated in vitro in rat cardiomyoblasts. After survivin transduction, survivin protein was detected in cell culture supernate confirming secretion of extracellular survivin. Under doxorubicin stimulation, survivin-transduced cells had significantly reduced apoptosis; however, incubation with survivin-conditioned media also showed reduced apoptosis that was absent with null-conditioned media. Doxorubicin-induced cardiomyopathy was established in Fischer rats. Subsets of animals underwent ultrasound-mediated survivin gene delivery or empty vector gene delivery at Week 3. Control rats received doxorubicin alone. Animals were studied using PCR, immunohistochemistry, echocardiography, and invasive haemodynamic studies out to Week 6. By Week 6, LV % fractional shortening by echocardiography and systolic function by pressure-volume loops were greater in survivin treated when compared with control- and empty-treated animals. There was reduced apoptosis by TUNEL and caspase activity in survivin-treated animals compared with control and empty treated at Week 4, with reduced interstitial fibrosis at Week 6.
  
  
  CONCLUSIONS
  Survivin gene therapy can attenuate the progression of LV systolic dysfunction in doxorubicin cardiomyopathy. This effect can be attributed to decreased myocyte apoptosis and prevention of maladaptive LV remodelling, by both direct myocyte transfection and potentially by paracrine mechanisms.
authors.affiliation: Division of Cardiology, Keenan Research Centre in the Li Ka Shing Knowledge Institute, 6-044 Donnelly Wing, St Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON, Canada M5B 1W8.
authors.forename: Paul J H
authors.initials: PJ
authors.lastname: Lee
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Rudenko
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kuliszewski
authors.forename: Christine
authors.initials: C
authors.lastname: Liao
authors.forename: M Golam
authors.initials: MG
authors.lastname: Kabir
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics; D002460:Cell Line; D004317:Doxorubicin / Q000633:toxicity*; D005355:Fibrosis / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000628:therapy*
chemical_list: C117749:Birc5 protein, mouse; C516989:Birc5 protein, rat; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin; D004317:Doxorubicin
keywords: Apoptosis; Cardiomyopathy; Gene therapy; Heart failure; Survivin