title: Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction.
abstract: Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control.
  
  
  RESULTS
  We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy.
  
  
  CONCLUSIONS
  Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration.
authors.affiliation: Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX, USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: The University of Texas Southwestern Medical Center at Dallas, Medical School, 5235 Harry Hine Blvd., Dallas, TX, USA.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, China.
authors.forename: Pintong
authors.initials: P
authors.lastname: Huang
authors.affiliation: Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX, USA.
authors.forename: Xing-Li
authors.initials: XL
authors.lastname: Meng
authors.affiliation: Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Clayton
authors.affiliation: Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX, USA.
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Shen
authors.affiliation: Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX, USA; Department of Internal Medicine, Division of Cardiology, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall St, Suite H030, Dallas, TX, USA. Electronic address: paulgr@baylorhealth.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grayburn
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics; D004317:Doxorubicin; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018014:Gene Transfer Techniques / Q000295:instrumentation; D015316:Genetic Therapy; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000378:metabolism; D045423:Microbubbles; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010957:Plasmids / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D014463:Ultrasonography / Q000295:instrumentation; D015854:Up-Regulation; D000071161:Forkhead Box Protein O1
chemical_list: D019938:Cyclin D1; D004317:Doxorubicin; D051858:Forkhead Transcription Factors; D052216:Glucagon-Like Peptide 1; D009419:Nerve Tissue Proteins; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
keywords: Adriamycin cardiomyopathy; Glucagon-like peptide-1; Myocardial regeneration; Piggybac transposon gene delivery plasmids; Ultrasound targeted microbubble destruction