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(Circulation. 2008;117:1563-1573.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Human Apolipoprotein A-I Gene Transfer Reduces the Development of Experimental Diabetic Cardiomyopathy

Sophie Van Linthout, PhD; Frank Spillmann, MD; Alexander Riad, MD; Christiane Trimpert, MSc; Joke Lievens, PhD; Marco Meloni, BS; Felicitas Escher, MD; Elena Filenberg, MD; Okan Demir, MD; Jun Li, MD; Mehdi Shakibaei, MD; Ingolf Schimke, MD, PhD; Alexander Staudt, MD; Stephan B. Felix, MD; Heinz-Peter Schultheiss, MD; Bart De Geest, MD, PhD; Carsten Tschöpe, MD

From Abteilung für Kardiologie und Pneumologie, Charité-Universitätsklinikum Berlin, Campus Benjamin Franklin, Berlin, Germany (S.V.L., F.S., A.R., M.M., F.E., E.F., O.D., H.-P.S., C. Tschöpe); Klinik für Innere Medizin B, Ernst-Moritz-Arndt-Universität, Greifswald, Germany (C. Trimpert, A.S., S.B.F.); Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium (J. Lievens, B.D.G.); Charité University Medicine Berlin, Campus Mitte, Center for Cardiovascular Research (J. Li) and Department of Cardiology (I.S.), Berlin, Germany; and Ludwig Maximilians University Munich, Faculty of Medicine, Institute of Anatomy, Musculoskeletal Research Group, Munich, Germany (M.S.).

Correspondence to Carsten Tschöpe, MD, Abteilung für Kardiologie und Pneumologie, Charité-Universitätsklinikum Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail carsten.tschoepe{at}charite.de

Received August 16, 2006; accepted January 18, 2008.

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.

Methods and Results— Intravenous GT with 3x10¹² 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).

Conclusion— ApoA-I GT reduced the development of streptozotocin-induced diabetic cardiomyopathy.

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