title: Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling.
abstract: BACKGROUND
  Studies in transgenic mice showed the key role of (Pim-1) (proviral integration site for Moloney murine leukemia virus-1) in the control of cardiomyocyte function and viability.
  
  
  OBJECTIVE
  We investigated whether Pim-1 represents a novel mechanistic target for the cure of diabetic cardiomyopathy, a steadily increasing cause of nonischemic heart failure.
  
  
  RESULTS
  In streptozotocin-induced type 1 diabetic mice, Pim-1 protein levels declined during progression of cardiomyopathy, along with upregulation of Pim-1 inhibitors, protein phosphatase 2A, and microRNA-1. Moreover, diabetic hearts showed low levels of antiapoptotic B-cell lymphoma-2 (Bcl-2) protein and increased proapoptotic caspase-3 activity. Studies on adult rat cardiomyocytes and murine cardiac progenitor cells challenged with high glucose confirmed the in vivo expressional changes. In rescue studies, anti-microRNA-1 boosted Pim-1 and Bcl-2 expression and promoted cardiomyocyte and cardiac progenitor cell survival under high glucose conditions. Similarly, transfection with Pim-1 plasmid prevented high glucose-induced cardiomyocyte and cardiac progenitor cell apoptosis. Finally, a single intravenous injection of human PIM-1 via cardiotropic serotype-9 adeno-associated virus (1 × 10(10) or 5 × 10(10) plaque-forming units per animal) at 4 weeks after diabetes induction led to sustained cardiac overexpression of Pim-1 and improved diastolic function and prevented left ventricular dilation and failure. Histological examination showed reduced cardiomyocyte apoptosis and fibrosis in association with increased c-kit(+) cells and cardiomyocyte proliferation, whereas molecular analysis confirmed activation of the prosurvival pathway and conservation of sarcoendoplasmic reticulum Ca(2+)-ATPase and α-myosin heavy chain in Pim-1-treated hearts.
  
  
  CONCLUSIONS
  Pim-1 downregulation contributes in the pathogenesis of diabetic cardiomyopathy. Systemic delivery of human PIM-1 via cardiotropic adeno-associated virus serotype-9 represents a novel and effective approach to treat diabetic cardiomyopathy.
authors.affiliation: Department of Experimental Cardiovascular Medicine, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.forename: Andrea
authors.initials: A
authors.lastname: Caporali
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.forename: Elisa
authors.initials: E
authors.lastname: Avolio
authors.forename: Graciela
authors.initials: G
authors.lastname: Sala-Newby
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Oikawa
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.forename: Antonio Paolo
authors.initials: AP
authors.lastname: Beltrami
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D005947:Glucose / Q000008:administration & dosage; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D010957:Plasmids / Q000008:administration & dosage; D051573:Proto-Oncogene Proteins c-pim-1 / Q000008:administration & dosage* / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D005947:Glucose