Gene transfer of extracellular SOD to the penis reduces O<UP><SUB>2</SUB><SUP>&minus;</SUP></UP>{middle dot} and improves erectile function in aged rats

doi:10.1152/ajpheart.00770.2002

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Gene transfer of extracellular SOD to the penis reduces O· and improves erectile function in aged rats

Trinity J. Bivalacqua¹^,², Jeffrey S. Armstrong³, John Biggerstaff⁴, Asim B. Abdel-Mageed¹^,², Philip J. Kadowitz², Wayne J. G. Hellstrom¹, and Hunter C. Champion⁵

Departments of ¹ Urology and ² Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112; ³ Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322; ⁴ Biomolecular Research Annex, University of Central Florida, Orlando, Florida 32816; and ⁵ Division of Cardiology, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland 21287

Increased superoxide anion (O·) may contribute to vascular dysfunction in aging. In aged cavernosaltissue, lucigenin-enhanced chemiluminescence demonstrated a threefoldincrease in superoxide formation, and the oxidative fluorescentprobe hydroethidine indicated higher superoxide levels throughoutthe aged penis. This increase in superoxide was associated withimpaired cavernosal nerve-mediated and agonist-induced erectileresponses, increased nitrotyrosine staining, and lower cGMP levels,but no compensatory change in cavernosal extracellular (EC)-superoxidedismutase (EC-SOD) mRNA or protein. In vivo adenoviral (Ad) genetransfer of EC-SOD to the penis resulted in higher expressionof EC-SOD mRNA, protein, SOD activity, cGMP levels, and lowernitrotyrosine staining. Transfection with AdCMVEC-SOD resultedin a significant increase in erectile response to cavernosal nervestimulation, ACh, and zaprinast to a magnitude similar to youngrats. These data provide evidence in support of the hypothesisthat erectile dysfunction associated with aging is related inpart to an increase in cavernosal O·formation. Gene-transfer of EC-SOD reduces superoxide formationand restores age-associated erectile function and may representa novel therapeutic target for the treatment of erectiledysfunction.

gene therapy; aging; nitric oxide; erectile dysfunction

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