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

一氧化氮可溶性鸟苷酸环化酶途径作为男性膀胱出口梗阻和衰老过程中下尿路症状的靶标

• 批准号: 10733864
• 负责人: Anthony John Kanai
• 金额: $ 69.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733864
• 关键词: 5 Alpha-Reductase Inhibitor; Adrenergic Receptor; Adult; Age; Aging; Apoptosis; Asian; BAX gene; BCL2 gene; Benign Prostatic Hypertrophy; Bladder; Cell Proliferation; Clinical; Clinical Research; Collagen; Combined Modality Therapy; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Disease Progression; Exhibits; Experimental Models; Extracellular Matrix; Fibrosis; Finasteride; Functional disorder; Health; Heme; Histologic; Hormonal; Housekeeping; Hyperplasia; Inflammation; Knock-out; Knockout Mice; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Medical; Modeling; Molecular; Mus; Muscle Tonus; Myofibroblast; Nerve; Nerve Degeneration; Neuronal Plasticity; Nitric Oxide; Obstruction; Operative Surgical Procedures; Oral; Outcome; Oxidative Stress; Oxidoreductase; Pathogenesis; Pathologic; Pathway interactions; Patients; Perfusion; Phenotype; Prostate; Prostatic; Prostatic Tissue; Prostatic hypertrophy; Refractory; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Soluble Guanylate Cyclase; Stanolone; Telemetry; Testing; Testosterone; Therapeutic Effect; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Tissues; Transforming Growth Factor beta; Up-Regulation; Urinary Retention; Urine; Urodynamics; age related; aged; antagonist; cGMP production; cardiovascular effects; conditional knockout; cytochrome b5 reductase; global health; heme a; inhibitor; lower urinary tract symptoms; male; men; mimetics; novel; overexpression; participant enrollment; phosphodiesterase V; pill; preference; pressure; prevent; protein activation; response; side effect; standard care; tadalafil; tamsulosin; urinary bladder neck

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.

抽象的 良性前列腺增生 (BPH) 是一种非常普遍的健康问题，约 50% 的男性在 50 岁之前就有这种症状，并且 80 岁时，75% 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（例如非那雄胺）以阻止转化 睾酮转变为更有效的二氢睾酮，以减少前列腺体积。然而，这些代理往往 无法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。多种证据表明，除了衰老之外，LUTS 的发病机制还包括 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”疗法，并强调 FDA 批准强调了对性副作用风险较低的治疗方案的偏好 磷酸二酯酶 5 抑制剂 (PDE5I)、他达拉非及其最近 (2021) 与非那雄胺的组合（即 Entadfi）作为治疗 BPH/LUTS 的单药。由于一些患者对他达拉非产生耐药性，因此存在 推进我们对一氧化氮 (NO•)-cGMP 信号传导在病理生理学中的理解有令人信服的理由 良性前列腺增生/尿路症状。 NO• 的典型靶点是可溶性鸟苷酸环化酶 (sGC)，它催化产生 环鸟苷酸生产规范。 sGC 的反应性取决于细胞色素 B5 还原酶 3 (CYB5R3)，该酶维持 sGC 血红素处于 NO• 敏感还原态 (Fe2+)。我们最近报道，老年（≥24 个月）雄性小鼠 无需激素操作即可重现膀胱压力高/尿流量低的 BOO 表型 与成年小鼠（9 个月）的低压/高流量以及每日口服 sGC 激活剂治疗相比， cinaciguat（10 mg/kg/2 周）逆转了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来测试我们的新假设，即 BPH/LUTS 出现在年龄的环境中。 相关的氧化应激会加剧产生 NO• 的（硝能）神经的神经变性，以及 炎症诱导的 CYB5R3 失活可减少 cGMP-PKG 信号传导。恶性前馈循环 BPH/LUTS 可以通过 cinaciguat 来规避，cinaciguat 是一种血红素模拟物，可以在以下情况下刺激 cGMP 产生： sGC 被氧化并且血红素被取代，而它与 PDE5I 的组合可以检查 PDE5 上调，因为 cGMP 的长期升高。我们在 CYB5R3 中的选择性敲除 (KO) 支持了这一点 前列腺/膀胱，这两种模型都与患有 BPH 的老年男性的前列腺组织进行比较。我们的目标是： 1）探讨NO•-sGC-cGMP信号通路在老年小鼠BPH/BOO/LUTS发病机制中的作用 西那西呱治疗； 2) 研究前列腺或膀胱中 CYB5R3 组织特异性缺失的影响 我们的条件 KO 小鼠； 3) 确定 cinaciguat/PDE5I 联合治疗是否可以覆盖 PDE5 过度表达导致对 PDE5Is 的耐药性以及可能发生的任何不良心血管影响 西那西呱。