Nitric Oxide-Soluble Guanylate Cyclase Pathway as a Target for Male Bladder Outlet Obstruction and Lower Urinary Tract Symptoms in Aging

摘要 良性前列腺增生（BPH）是一种高度流行的健康问题，约50%的50岁男性表现出这种问题， 75%至80岁，可能与膀胱出口梗阻（BOO）和下尿路症状有关 （LUTS）。一线治疗包括α1-肾上腺素受体拮抗剂（例如，坦索罗辛）以减少平滑肌 前列腺和膀胱颈的张力和5α-还原酶抑制剂（例如，financede）到block的转换 睾酮到更有效的双氢睾酮，以减少前列腺体积。然而，这些代理人往往 不能有效预防疾病进展为尿潴留，这可能需要手术干预， 很多病人。多种证据支持，除了衰老，LUTS的发病机制包括 多种可改变的因素包括前列腺灌注受损，氧化应激介导的炎症， 纤维化和神经可塑性。临床证据反对“一刀切”的治疗，并强调 FDA批准强调的性副作用风险较低的治疗选择偏好 磷酸二酯酶-5抑制剂（PDE 5I）他达拉非及其最近（2021年）与非那肽的联合用药（即， Entadfi）作为BPH/LUTS的单一药丸。由于一些患者对他达拉非不应， 一个令人信服的理由，以促进我们的理解一氧化氮（NO·）-cGMP信号转导的病理生理学， BPH/LUTS。NO·的典型靶标是可溶性鸟苷酸环化酶（sGC），其催化 cGMP。sGC的反应性依赖于细胞色素B5还原酶-3（CYB 5 R3）， sGC血红素处于NO·敏感的还原态（Fe ~（2+））。我们最近报道，老年（≥24个月）雄性小鼠， 在没有激素控制的情况下，概括了高膀胱压/低尿流的BOO表型 与低压/高流量成年小鼠（9个月）和每天口服sGC激活剂相比， 西那西呱（10 mg/kg/2周）逆转这些老年小鼠的前列腺增生和BOO。我们建议 老年小鼠是一个合适的模型，用于测试我们的新假设，即BPH/LUTS出现在年龄的环境中， 相关的氧化应激增强NO·产生（氮能）神经的神经变性， 炎症诱导的CYB 5 R3失活以减少cGMP-PKG信号传导。前馈恶性循环 的BPH/LUTS可以通过西那西呱来规避，西那西呱是一种血红素模拟物，当 sGC被氧化，血红素被置换，而其与PDE 5I的组合可以检查PDE 5的上调， 持续升高的cGMP。这一点得到了我们的CYB 5 R3选择性敲除（KO）的支持。 前列腺/膀胱，将两种模型与患有BPH的老年男性的前列腺组织进行比较。我们的目标是： 1)NO·-sGC-cGMP信号通路在老年小鼠BPH/BOO/LUTS发病机制中的作用 2）研究前列腺或膀胱中CYB 5 R3的组织特异性缺失对前列腺癌的影响， 我们的条件性KO小鼠;和3）确定西那西呱/PDE 5I组合疗法是否可以超越PDE 5 过度表达导致的对PDE 5I的不应性和可能发生的任何不利的心血管作用， 西纳西瓜特。

Abstract Benign Prostatic Hyperplasia (BPH) is a highly prevalent health issue exhibited by ~50% of men by age 50, and 75% by age 80 which may be associated with bladder outlet obstruction (BOO) and lower urinary tract symptoms (LUTS). First line treatments include α1-adrenoceptors antagonists (e.g., tamsulosin) to decrease smooth muscle tone in the prostate and bladder neck and 5α-reductase inhibitors (e.g., finasteride) to block conversion of testosterone to more potent dihydrotestosterone for reducing prostate volume. However, these agents are often ineffective in preventing disease progression to urinary retention which may necessitate surgical intervention in many patients. Multiple lines of evidence support that apart from aging, the pathogenesis of LUTS comprises multiple modifiable factors including compromised prostatic perfusion, oxidative stress mediated inflammation, fibrosis, and neuroplasticity. Clinical evidence argues against “one size fits all” therapy and highlights the preference of treatment options with lower risk of sexual side effects which is underscored by the FDA approval of phosphodiesterase-5 inhibitor (PDE5I), tadalafil, and its recent (2021) combination with finasteride (i.e., Entadfi) as a single pill for BPH/LUTS. Since some patients develop refractoriness to tadalafil, there is a compelling reason to advance our understanding of nitric oxide (NO•)-cGMP signaling in the pathophysiology of BPH/LUTS. The canonical target for NO• is soluble guanylate cyclase (sGC) that catalyzes the production of cGMP. The responsiveness of sGC is dependent upon cytochrome B5 reductase-3 (CYB5R3) that maintains the sGC heme in the NO• sensitive reduced state (Fe2+). We recently reported that aged (≥24 mo) male mice without hormonal manipulation recapitulate the BOO phenotype of high bladder pressure/low urine flow compared to low pressure/high flow of adult mice (9 mo), and that daily oral treatment with the sGC activator, cinaciguat (10 mg/kg/2 wks) reversed prostate hyperplasia and BOO in these aged mice. We propose that the aged mouse is a suitable model for testing our novel hypothesis that BPH/LUTS arises in the milieu of age- related oxidative stress potentiating the neurodegeneration of NO• producing (nitrergic) nerves and inflammation-induced inactivation of CYB5R3 to decrease cGMP-PKG signaling. The vicious feed forward cycle of BPH/LUTS can be circumvented by cinaciguat, a heme mimetic that can stimulate cGMP production when sGC is oxidized and the heme displaced, while its combination with a PDE5I can check PDE5 upregulation due to prolonged elevation of cGMP. This is supported by our selective knockout (KO) of CYB5R3 in the prostate/bladder, with both models to be compared with prostatic tissue from aged men with BPH. Our aims are: 1) Probe the role of the NO•-sGC-cGMP signaling pathway in the pathogenesis of BPH/BOO/LUTS in aged mice with cinaciguat treatment; 2) Study the impact of tissue specific deletion of CYB5R3 in the prostate or bladder in our conditional KO mouse; and 3) Determine if cinaciguat/PDE5I combination therapy can override PDE5 overexpression driven refractoriness to PDE5Is and any untoward cardiovascular effects that may occur with cinaciguat.