In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 117, No. 12 ( 2008-03-25), p. 1563-1573
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. Methods and Results— Intravenous GT with 3×10 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-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.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/CIRCULATIONAHA.107.710830
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2008
detail.hit.zdb_id:
1466401-X
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