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Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425
Adrenomedullin (AM) is a potent
vasodilating peptide and is involved in cardiovascular and renal
disease. In the present study, we investigated the role of AM in
cardiac and renal function in streptozotocin (STZ)-induced diabetic
rats. A single tail-vein injection of adenoviral vectors harboring the
human AM gene (Ad.CMV-AM) was administered to the rats 1-wk post-STZ
treatment (65 mg/kg iv). Immunoreactive human AM was detected in the
plasma and urine of STZ-diabetic rats treated with Ad.CMV-AM.
Morphological and chemical examination showed that AM gene delivery
significantly reduced glycogen accumulation within the hearts of
STZ-diabetic rats. AM gene delivery improved cardiac function compared
with STZ-diabetic rats injected with control virus, as observed by decreased left ventricular end-diastolic pressure, increased cardiac output, cardiac index, and heart rate. AM gene transfer significantly increased left ventricular long axis (11.69 ± 0.46 vs. 10.31 ± 0.70 mm, n = 10, P < 0.05) and rate of
pressure rise and fall (+6,090.1 ± 597.3 vs. +4,648.5 ± 807.1 mmHg/s), (
4,902.6 ± 644.2 vs.
3,915.5 ± 805.8 mmHg/s,
n = 11, P < 0.05). AM also significantly attenuated renal glycogen accumulation and tubular damage in
STZ-diabetic rats as well as increased urinary cAMP and cGMP levels,
along with increased cardiac cAMP and Akt phosphorylation. We also
observed that delivery of the AM gene caused an increase in body weight along with phospho-Akt and membrane-bound GLUT4 levels in skeletal muscle. These results suggest that AM plays a protective role in
hyperglycemia-induced glycogen accumulation and cardiac and renal
dysfunction via Akt signal transduction pathways.
streptozotocin; adrenomedullin; gene delivery; adenovirus
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