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1 Brady Urological Institute, Johns Hopkins Hospital, baltimore, Maryland, United States
2 Department of Urology, Tulane Medical Center, New Orleans, Louisiana, United States
3 Medicine, Johns Hopkins University, Baltimore, Maryland, United States; Urology, Johns Hopkins University, Baltimore, Maryland, United States; Urology, Tulane University, New Orleans, Maryland, United States
* To whom correspondence should be addressed. E-mail: hcc{at}jhmi.edu.
As both increased nitric oxide synthase (NOS) abundance and diminished nitric oxide (NO) signaling have been reported in the aging penis, the role of NO in the adaptations of aging remain controversial. Here we tested the hypothesis that arginase, enzyme that competes with NOS for the substrate L-arginine, contributes to erectile dysfunction (ED) with advanced age in the B6/129 strain of mouse. Arginase protein abundance, mRNA expression, and enzyme activity were elevated in aged compared with young penile endothelial cells. In addition, endothelial NOS (NOS3) protein abundance was greater in aged vs young penile endothelial cells while NOS activity and cGMP levels were reduced. Calcium-dependent conversion of L-arginine to L-citrulline and cGMP formation increased significantly in the aged mouse penes in the presence of the arginase inhibitor, 2(S)-amino-6-boronohexanoic acid (ABH). However, there was no effect on L-arginine to L-citrulline conversion or cGMP accumulation in the endothelium from young mouse penes. To assess the functional role of arginase in the inhibition of NOS pathway responsiveness in the penis, we evaluated the effects of ABH and an adeno-associated virus encoding an antisense sequence to arginase I (AAVAnti-Arginase) on erectile function in vivo. ABH and AAVAnti-Arginase enhanced endothelium-dependent erectile responses in the aged mice without altering endothelium-independent responses. Paralleling our in vitro observations, ABH or AAVAnti-Arginase did not affect vascular responses in the young mice. Inhibition of the arginase pathway improves endothelial function in the aging penile circulation, suggesting that the arginase pathway may be exploited to improve ED-associated with aging.
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