Gene transfer of extracellular SOD to the penis reduces O2-* and improves erectile function in aged rats.
Increased superoxide anion (O(2)(-).) may contribute to vascular dysfunction in aging. In aged cavernosal tissue, lucigenin-enhanced chemiluminescence demonstrated a threefold increase in superoxide formation, and the oxidative fluorescent probe hydroethidine indicated higher superoxide levels throughout the aged penis. This increase in superoxide was associated with impaired cavernosal nerve-mediated and agonist-induced erectile responses, increased nitrotyrosine staining, and lower cGMP levels, but no compensatory change in cavernosal extracellular (EC)-superoxide dismutase (EC-SOD) mRNA or protein. In vivo adenoviral (Ad) gene transfer of EC-SOD to the penis resulted in higher expression of EC-SOD mRNA, protein, SOD activity, cGMP levels, and lower nitrotyrosine staining. Transfection with AdCMVEC-SOD resulted in a significant increase in erectile response to cavernosal nerve stimulation, ACh, and zaprinast to a magnitude similar to young rats. These data provide evidence in support of the hypothesis that erectile dysfunction associated with aging is related in part to an increase in cavernosal O(2)(-). formation. Gene-transfer of EC-SOD reduces superoxide formation and restores age-associated erectile function and may represent a novel therapeutic target for the treatment of erectile dysfunction.
Bivalacqua
Trinity J
TJ
Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Armstrong
Jeffrey S
JS
Biggerstaff
John
J
Abdel-Mageed
Asim B
AB
Kadowitz
Philip J
PJ
Hellstrom
Wayne J G
WJ
Champion
Hunter C
HC
D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D010410:Penile Erection / Q000502:physiology*; D010413:Penis / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011914:Rats, Inbred BN; D011993:Recombinant Fusion Proteins; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase; D001616:beta-Galactosidase; D006152:Cyclic GMP