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Post-Translational Modification of Neuronal Nitric Oxide Synthase in the Human Erectile Tissue Following Radical Prostatectomy

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Sources of Funding: none

Introduction

Erectile dysfunction (ED) is a highly prevalent complication of radical prostatectomy (RP) with a reported incidence as high as 90%. Our previous studies in a rat model of bilateral cavernous nerve injury, which mimics nerve injury following RP, showed that neuronal nitric oxide synthase (nNOS) phosphorylation and uncoupling occurs in association with increased oxidative stress in the penis. However, the mechanisms of nNOS regulation in RP-associated ED in humans are poorly understood. We evaluated the effect of RP-associated cavernous nerve injury on nNOS post-translational modification in human erectile tissue.

Methods

Human erectile tissue was obtained from 6 patients with RP-associated ED (median age: 60 [50-71] years) (53.5 months [22-117] after RP) and from 4 patients with non-ED Peyronie&[prime]s disease (median age: 57.5 [53-59] years) as controls. RP group had severe ED (SHIM (The Sexual Health Inventory for Men) score=1 [1-2]) (preop RP SHIM score=22 [18-25]). Peyronie&[prime]s disease patients in control group did not have ED based on SHIM score (SHIM > 21) and penile doppler ultrasonography results. No patients in either group had comorbidities such as diabetes mellitus, hypertension, hypercholesterolemia or cardiovascular diseases. Samples were collected for molecular analyses of nNOS phosphorylation on activating (Ser-1412) and inhibitory (Ser-847) site, total nNOS expression, nNOS uncoupling (source of oxidative stress), caveolin-1 binding to nNOS (which decreases nNOS activity) and P-VASP Ser-239 (which indicates the integrity of nitric oxide signalling) by Western blot.

Results

nNOS protein expression was decreased (p<0.05) in RP group compared to Control group. nNOS phosphorylation on positive (Ser-1412) regulatory site was decreased (p<0.05) while phosphorylation on negative (Ser-847) regulatory site was increased (p<0.05) in RP group compared to Control group. Caveolin-1 binding to nNOS was increased (p<0.05), while P-VASP (Ser-239) expression was decreased (p<0.05) in RP group compared to Control group. nNOS uncoupling was not different between groups.

Conclusions

nNOS function in the penis is impaired by deranged phosphorylation and increased binding Caveolin-1 to nNOS, conceivably resulting in ED in the face of RP. Our description of molecular factors contributing to the pathogenesis of RP-associated ED at the human level is relevant for advancing clinically therapeutic approaches to restore erectile function in RP patients.

Funding

none

Authors
Serkan Karakus
Biljana Musicki
Arthur L. Burnett
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