Superoxide anion production in the rat penis impairs erectile function in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy.
BACKGROUND
Superoxide anion may contribute to erectile dysfunction (ED) in diabetes mellitus by reducing cavernosal nitric oxide (NO) bioavailability. The purpose of this study was to determine if gene transfer of extracellular superoxide dismutase (EC-SOD) can reduce superoxide anion formation and determine if this reactive oxygen species may contribute to diabetes-related ED in an experimental model of diabetes.


METHODS
Three groups of animals were utilized: (1) control; (2) streptozotocin (STZ)-diabetic rats [60 mg/kg intraperitoneally (ip)] intracavernosally injected with AdCMVbetagal (negative control); and (3) STZ-rats intracavernosally injected with AdCMVEC-SOD. Two months after ip injection of STZ, groups 2 and 3 were transfected with the adenoviruses and 2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Confocal microscopy for superoxide anion and von Willebrand Factor (vWF) was performed in the STZ-diabetic rat. Superoxide anion production, total SOD activity, and cyclic guanosine monophosphate (cGMP) levels were measured in each experimental group of rats.


RESULTS
Confocal microscopy demonstrated superoxide in smooth muscle and endothelial cells of the STZ-rat cavernosum and colocalized with vWF in the endothelium. Higher superoxide anion levels and decreased cGMP levels were found in the penis of STZ-rats at a time when erectile function was reduced. Two days after administration of AdCMVEC-SOD, superoxide anion levels were significantly lower in the penis of STZ-rats. Total SOD activity and cavernosal cGMP was increased in the penis of EC-SOD-transfected rats. STZ-rats transfected with AdCMVEC-SOD had a peak intracavernosal pressure (ICP) and total ICP to CNS that was similar to control rats.


CONCLUSIONS
These data demonstrate that in vivo adenoviral gene transfer of EC-SOD can reduce corporal superoxide anion levels and raise cavernosal cGMP levels by increasing NO bioavailability thus restoring erectile function in the STZ-diabetic rat.
Bivalacqua
Trinity J
TJ
Johns Hopkins Hospital, Brady Urological Institute, Baltimore, MD, USA. tbivala@jhmi.edu
Usta
Mustafa F
MF
Kendirci
Muammer
M
Pradhan
Leena
L
Alvarez
Xavier
X
Champion
Hunter C
HC
Kadowitz
Philip J
PJ
Hellstrom
Wayne J G
WJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000378:metabolism; D007172:Erectile Dysfunction / Q000378:metabolism*; D015316:Genetic Therapy; D006157:Guanosine Monophosphate / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010413:Penis / Q000294:innervation / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000235:genetics / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D014162:Transfection
D017382:Reactive Oxygen Species; D013481:Superoxides; D013311:Streptozocin; D006157:Guanosine Monophosphate; D013482:Superoxide Dismutase