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.
