Benign Prostatic Hyperplasia (BPH) is a prevalent condition in aging men that can promote development of lower urinary tract symptoms and dysfunction. The underlying causes for BPH are multifactorial and previous studies have implicated a regulatory role of nitric oxide-soluble guanylate cyclase (sGC) signaling on prostate glandular growth and extracellular matrix deposition. It is hypothesized that sGC activity is adversely affected due to increased oxidative stress that is common in aging, thus, to determine how sGC signaling is downregulated we evaluated the expression of protein intermediates of the pathway in aged mouse prostates and changes induced by a two-week treatment with the small molecule sGC activator, cinaciguat.

Young adult (2-4 months) and aged (>21 months) male C57Bl/6 mice were implanted with subcutaneous osmotic pumps to deliver 10 mg/kg/day of cinaciguat or vehicle for a two-week period. Mice were sacrificed at the end of treatments and prostate tissue collected and protein lysates obtained for standard immunoblot protocol. The abundance of target proteins analyzed relative to beta-actin loading control with each normalized to total protein.

In aged mice, the expression of sGCalpha1 was increased (Figure 1A) and 1 subunit was decreased (Figure 1B) in prostate tissues compared to that of younger mice. Aged mice treated with cinaciguat showed a reduction in sGCalpha1 but not that of beta1. This correlated with increased levels of JNK, a transcription factors that regulate stress responses (Figure 1C) that was reduced with cinaciguat treatment.

Aging can alter the fundamental components of the nitric oxide signaling pathway through multiple mechanisms. Cinaciguat treatment normalized the sGCalpha1 subunit ratio to that of younger mouse prostates, which is also associated with decreased inflammation and proliferation. Previous reports have indicated sGCalpha1 subunit can directly bind to the cell cycle regulator, p53, to promote proliferation [1]. Further, JNK activation can increase Bcl-2 mediated cell survival [2] which has previously been shown to be a key component of BPH pathophysiology [3]. To our knowledge, alterations in sGC subunit composition as a driver of BPH pathology has not been demonstrated and could indicate a novel therapeutic mode of action for sGC activators.

Aging inhibits the nitric oxide-sGC pathway in the prostate and contributes to cell proliferation and inflammation. Treatments that target and reestablish normal nitric oxide signaling could represent a non-invasive treatment for BPH.

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