title: Intramyocardial injection of SERCA2a-expressing lentivirus improves myocardial function in doxorubicin-induced heart failure.
abstract: BACKGROUND
  Doxorubicin is an effective anticancer drug. The major limitation to its use is the induction of dose-dependent cardiomyopathy. No specific treatment exists for doxorubicin-induced cardiomyopathy and treatments used for other forms of heart failure have only limited beneficial effects. The contraction-relaxation cycle of the heart is controlled by cytosolic calcium concentrations, which, in turn, are critically regulated by the activity of the sarcoplasmic reticulum Ca(2) (+) ATPase (SERCA2a) pump. We hypothesized that SERCA2a gene transfer would ameliorate doxorubicin-induced cardiomyopathy.
  
  
  METHODS
  Lentiviral vectors LV-SERCA2a-GFP and LV-GFP were constructed and in vitro gene transfer of LV-SERCA2a-GFP confirmed SERCA2a expression by western blot analysis. Heart failure was induced by giving a single intraperitoneal injection of doxorubicin. LV-SERCA2a-GFP, LV-GFP vectors and phosphate-buffered saline (PBS) were injected under echocardiographic control to the anterior wall of the left ventricle.
  
  
  RESULTS
  Echocardiography analyses were performed on the injection day and 28 days postinjection. On the injection day, there were no significant differences in the average ejection fractions (EFs) among SERCA2a (40.0%), GFP (41.1%) and PBS (39.4%) injected animals. On day 28, EF in the SERCA2a group had increased by 16.6 ± 6.7% to 46.4 ± 2.1%. By contrast, EFs in the GFP (40.2 ± 1.3%) and PBS (40.6 ± 1.4%) groups remained at pre-injection levels. In addition, end systolic and end diastolic left ventricle volumes were significantly smaller in the SERCA2a group compared to controls.
  
  
  CONCLUSIONS
  SERCA2a gene transfer significantly improves left ventricle function and dimensions in doxorubicin-induced cardiomyopathy, thus making LV-SERCA2a gene transfer an attractive treatment modality for doxorubicin-induced heart failure. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.|Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.|Drug Research Doctoral Program, University of Turku, Turku, Finland.
authors.forename: Minttu
authors.initials: M
authors.lastname: Mattila
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.|Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, University of Turku, Turku, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Koskenvuo
authors.affiliation: Department of Pathology, Turku University Hospital, University of Turku, Turku, Finland.
authors.forename: Mirva
authors.initials: M
authors.lastname: Söderström
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.|Drug Research Doctoral Program, University of Turku, Turku, Finland.
authors.forename: Kim
authors.initials: K
authors.lastname: Eerola
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.|Heart Centre, Turku University Hospital, University of Turku, Turku, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Savontaus
mesh_terms: D000818:Animals; D004317:Doxorubicin; D004452:Echocardiography; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D057809:HEK293 Cells; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004317:Doxorubicin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: SERCA2a; doxorubicin; gene therapy; heart failure; lentivirus