TY - JOUR
T1 - Priapism in a Fabry disease mouse model is associated with upregulated penile nNOS and eNOS expression
AU - Meng, Xing Li
AU - Arning, Erland
AU - Wight-Carter, Mary
AU - Day, Taniqua S.
AU - Jabbarzadeh-Tabrizi, Siamak
AU - Chen, Shuyuan
AU - Ziegler, Robin J.
AU - Bottiglieri, Teodoro
AU - Schneider, Jay W.
AU - Cheng, Seng H.
AU - Schiffmann, Raphael
AU - Shen, Jin Song
N1 - Funding Information:
Acknowledgements We thank Sean C. Goetsch and Misty N. Demaree (University of Texas Southwestern Medical Center, Dallas), Deborah L. Berry (Georgetown University Medical Center, Washington D.C.) and Dilechia Hawthorne (Baylor Research Institute, Dallas) for their technical assistance. We thank Marie-Anne Schiffmann for editing and proofing the manuscript. This work was supported by the Baylor Scott & White Research Institute Foundation.
Funding Information:
Funding This work was supported by the Baylor Scott & White Research Institute Foundation. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.
Publisher Copyright:
© 2017, SSIEM.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Fabry disease is a glycosphingolipidosis caused by deficient activity of α-galactosidase A; it is one of a few diseases that are associated with priapism, an abnormal prolonged erection of the penis. The goal of this study was to investigate the pathogenesis of Fabry disease-associated priapism in a mouse model of the disease. We found that Fabry mice develop late-onset priapism. Neuronal nitric oxide synthase (nNOS), which was predominantly present as the 120-kDa N-terminus-truncated form, was significantly upregulated in the penis of 18-month-old Fabry mice compared to wild type controls (~fivefold). Endothelial NOS (eNOS) was also upregulated (~twofold). NO level in penile tissues of Fabry mice was significantly higher than wild type controls at 18 months. Gene transfer-mediated enzyme replacement therapy reversed abnormal nNOS expression in the Fabry mouse penis. The penile nNOS level was restored by antiandrogen treatment, suggesting that hyperactive androgen receptor signaling in Fabry mice may contribute to nNOS upregulation. However, the phosphodiesterase-5A expression level and the adenosine content in the penis, which are known to play roles in the development of priapism in other etiologies, were unchanged in Fabry mice. In conclusion, these data suggested that increased nNOS (and probably eNOS) content and the consequential elevated NO production and high arterial blood flow in the penis may be the underlying mechanism of priapism in Fabry mice. Furthermore, in combination with previous findings, this study suggested that regulation of NOS expression is susceptible to α-galactosidase A deficiency, and this may represent a general pathogenic mechanism of Fabry vasculopathy.
AB - Fabry disease is a glycosphingolipidosis caused by deficient activity of α-galactosidase A; it is one of a few diseases that are associated with priapism, an abnormal prolonged erection of the penis. The goal of this study was to investigate the pathogenesis of Fabry disease-associated priapism in a mouse model of the disease. We found that Fabry mice develop late-onset priapism. Neuronal nitric oxide synthase (nNOS), which was predominantly present as the 120-kDa N-terminus-truncated form, was significantly upregulated in the penis of 18-month-old Fabry mice compared to wild type controls (~fivefold). Endothelial NOS (eNOS) was also upregulated (~twofold). NO level in penile tissues of Fabry mice was significantly higher than wild type controls at 18 months. Gene transfer-mediated enzyme replacement therapy reversed abnormal nNOS expression in the Fabry mouse penis. The penile nNOS level was restored by antiandrogen treatment, suggesting that hyperactive androgen receptor signaling in Fabry mice may contribute to nNOS upregulation. However, the phosphodiesterase-5A expression level and the adenosine content in the penis, which are known to play roles in the development of priapism in other etiologies, were unchanged in Fabry mice. In conclusion, these data suggested that increased nNOS (and probably eNOS) content and the consequential elevated NO production and high arterial blood flow in the penis may be the underlying mechanism of priapism in Fabry mice. Furthermore, in combination with previous findings, this study suggested that regulation of NOS expression is susceptible to α-galactosidase A deficiency, and this may represent a general pathogenic mechanism of Fabry vasculopathy.
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U2 - 10.1007/s10545-017-0107-6
DO - 10.1007/s10545-017-0107-6
M3 - Article
C2 - 29110178
AN - SCOPUS:85033482826
SN - 0141-8955
VL - 41
SP - 231
EP - 238
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 2
ER -