Human apolipoprotein A-I gene transfer reduces the development of experimental diabetic cardiomyopathy

Article

关键词: HIGH-DENSITY-LIPOPROTEIN;    LEFT-VENTRICULAR DYSFUNCTION;    KALLIKREIN-KININ SYSTEM;    CORONARY-HEART-DISEASE;    NECROSIS-FACTOR-ALPHA;    CASPASE-3 ACTIVATION;    SUPEROXIDE-DISMUTASE;    INDUCED APOPTOSIS;    OXIDATIVE STRESS;    ENDOTHELIAL-CELL;   

DOI  :  10.1161/CIRCULATIONAHA.107.710830

来源: SCIE

【 摘 要 】

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 3 x 10(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-IGT 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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