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Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction
Author(s) -
Musicki B.,
Burnett A. L.
Publication year - 2017
Publication title -
andrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.947
H-Index - 43
eISSN - 2047-2927
pISSN - 2047-2919
DOI - 10.1111/andr.12313
Subject(s) - nitrotyrosine , nadph oxidase , oxidative stress , erectile dysfunction , endocrinology , medicine , nitric oxide synthase , endothelial nos , downregulation and upregulation , oxidative phosphorylation , chemistry , nitric oxide , biochemistry , enos , gene
Summary Erectile dysfunction ( ED ) associated with type 2 diabetes mellitus (T2 DM ) involves dysfunctional nitric oxide ( NO ) signaling and increased oxidative stress in the penis. However, the mechanisms of endothelial NO synthase (e NOS ) and neuronal NO synthase (n NOS ) dysregulation, and the sources of oxidative stress, are not well defined, particularly at the human level. The objective of this study was to define whether uncoupled e NOS and n NOS , and NADPH oxidase upregulation, contribute to the pathogenesis of ED in T2 DM men. Penile erectile tissue was obtained from 9 T2 DM patients with ED who underwent penile prosthesis surgery for ED , and from six control patients without T2 DM or ED who underwent penectomy for penile cancer. The dimer‐to‐monomer protein expression ratio, an indicator of uncoupling for both e NOS and n NOS , total protein expressions of e NOS and n NOS , as well as protein expressions of NADPH oxidase catalytic subunit gp91phox (an enzymatic source of oxidative stress) and 4‐hydroxy‐2‐nonenal [4‐ HNE ] and nitrotyrosine (markers of oxidative stress) were measured by western blot in this tissue. In the erectile tissue of T2 DM men, e NOS and n NOS uncoupling and protein expressions of NADPH oxidase subunit gp91phox, 4‐ HNE ‐ and nitrotyrosine‐modified proteins were significantly ( p < 0.05) increased compared to control values. Total e NOS and n NOS protein expressions were not significantly different between the groups. In conclusion, mechanisms of T2 DM ‐associated ED in the human penis may involve uncoupled e NOS and n NOS and NADPH oxidase upregulation. Our description of molecular factors contributing to the pathogenesis of T2 DM ‐associated ED at the human level is relevant to advancing clinically therapeutic approaches to restore erectile function in T2DM patients.