title: Human apolipoprotein A-I gene transfer reduces the development of experimental diabetic cardiomyopathy.
abstract: BACKGROUND
  The hallmarks of diabetic cardiomyopathy are cardiac oxidative stress, intramyocardial inflammation, cardiac fibrosis, and cardiac apoptosis. Given the antioxidative, antiinflammatory, and antiapoptotic potential of high-density lipoprotein (HDL), we evaluated the hypothesis that increased HDL via gene transfer (GT) with human apolipoprotein (apo) A-I, the principal apolipoprotein of HDL, may reduce the development of diabetic cardiomyopathy.
  
  
  RESULTS
  Intravenous GT with 3x10(12) particles/kg of the E1E3E4-deleted vector Ad.hapoA-I, expressing human apoA-I, or Ad.Null, containing no expression cassette, was performed 5 days after streptozotocin (STZ) injection. Six weeks after apoA-I GT, HDL cholesterol levels were increased by 1.6-fold (P<0.001) compared with diabetic controls injected with the Ad.Null vector (STZ-Ad.Null). ApoA-I GT and HDL improved LV contractility in vivo and cardiomyocyte contractility ex vivo, respectively. Moreover, apoA-I GT was associated with decreased cardiac oxidative stress and reduced intramyocardial inflammation. In addition, compared with STZ-Ad.Null rats, cardiac fibrosis and glycogen accumulation were reduced by 1.7-fold and 3.1-fold, respectively (P<0.05). Caspase 3/7 activity was decreased 1.2-fold (P<0.05), and the ratio of Bcl-2 to Bax was upregulated 1.9-fold (P<0.005), translating to 2.1-fold (P<0.05) reduced total number of cardiomyocytes with apoptotic characteristics and 3.0-fold (P<0.005) reduced damaged endothelial cells compared with STZ-Ad.Null rats. HDL supplementation ex vivo reduced hyperglycemia-induced cardiomyocyte apoptosis by 3.4-fold (P<0.005). The apoA-I GT-mediated protection was associated with a 1.6-, 1.6-, and 2.4-fold induction of diabetes-downregulated phospho to Akt, endothelial nitric oxide synthase, and glycogen synthase kinase ratio, respectively (P<0.005).
  
  
  CONCLUSIONS
  ApoA-I GT reduced the development of streptozotocin-induced diabetic cardiomyopathy.
authors.affiliation: Abteilung für Kardiologie und Pneumologie, Charité-Universitätsklinikum Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Linthout
authors.forename: Frank
authors.initials: F
authors.lastname: Spillmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Christiane
authors.initials: C
authors.lastname: Trimpert
authors.forename: Joke
authors.initials: J
authors.lastname: Lievens
authors.forename: Marco
authors.initials: M
authors.lastname: Meloni
authors.forename: Felicitas
authors.initials: F
authors.lastname: Escher
authors.forename: Elena
authors.initials: E
authors.lastname: Filenberg
authors.forename: Okan
authors.initials: O
authors.lastname: Demir
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Ingolf
authors.initials: I
authors.lastname: Schimke
authors.forename: Alexander
authors.initials: A
authors.lastname: Staudt
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Bart
authors.initials: B
authors.lastname: De Geest
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage* / Q000235:genetics; D009202:Cardiomyopathies / Q000517:prevention & control* / Q000628:therapy; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D008055:Lipids; D008075:Lipoproteins, HDL; D017392:Thiobarbituric Acid Reactive Substances; D013311:Streptozocin