Human apolipoprotein A-I gene transfer reduces the development of experimental diabetic cardiomyopathy.
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.
Van Linthout
Sophie
S
Abteilung für Kardiologie und Pneumologie, Charité-Universitätsklinikum Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Spillmann
Frank
F
Riad
Alexander
A
Trimpert
Christiane
C
Lievens
Joke
J
Meloni
Marco
M
Escher
Felicitas
F
Filenberg
Elena
E
Demir
Okan
O
Li
Jun
J
Shakibaei
Mehdi
M
Schimke
Ingolf
I
Staudt
Alexander
A
Felix
Stephan B
SB
Schultheiss
Heinz-Peter
HP
De Geest
Bart
B
Tschöpe
Carsten
C
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
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D008055:Lipids; D008075:Lipoproteins, HDL; D017392:Thiobarbituric Acid Reactive Substances; D013311:Streptozocin