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）是约50％到50岁的男性暴露的一个高度普遍的健康问题， 75％到80岁，可能与膀胱出口异常（嘘）和较低的尿道符号有关 （luts）。第一行处理包括α1-肾上腺素受体拮抗剂（例如，tamsulosin）减少平滑肌 前列腺和膀胱颈和5α-还原酶抑制剂（例如非那雄胺）中的音调以阻止 睾丸激素，可减少前列腺量的更多潜在二氢睾丸激素。但是，这些代理通常是 无效预防疾病进展为尿retention留，这可能需要手术干预 许多患者。多种证据支持除衰老外，LUTS的发病机理包括 多种可修改因素，包括造成的前列腺灌注，氧化应激介导的注射， 纤维化和神经可塑性。临床证据反对“适合所有人”疗法的论点，并突出显示 偏爱治疗方案的性副作用风险较低，这是FDA批准强调的 磷酸二酯酶5抑制剂（PDE5I），他达拉非及其最近（2021年）与非那雄胺的组合（即 Entadfi）作为BPH/LUTS的单一药丸。由于一些患者对他达拉非的难治性，因此有一个 令人信服的理由推进我们对一氧化氮（NO•）-CGMP信号传导的理解 BPH/LUTS。 NO的规范目标•是固体鸟烯酸酯环化酶（SGC），它催化产生的产生 CGMP。 SGC的响应能力取决于维持维持的细胞色素B5降低-3（CYB5R3） NO•敏感降低状态（Fe2+）中的SGC血红素。我们最近报道了年龄（≥24o）雄性小鼠 没有激素操纵，概括了高膀胱压力/低尿液流量的BOO表型 与成年小鼠的低压/高流量相比，每天用SGC激活剂进行口服处理 cinaciguat（10 mg/kg/2 wks）在这些老鼠中逆转了前列腺增生和嘘声。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，即在年龄的环境中出现了BPH/LUTS。 相关的氧化应激电位NO•产生（硝化）神经和 炎症引起的CYB5R3失活以减少CGMP-PKG信号传导。恶性饲料前循环 Cinaciguat可以绕过BPH/LUTS的bph/luts，这是一种血红素模拟物，可以刺激CGMP的产生 SGC被氧化并流离失所，而其与PDE5I的组合可以检查PDE5上调 长时间升高CGMP。这是由我们在CYB5R3的选择性淘汰（KO）支持的 前列腺/膀胱，两种模型均应与BPH老年男性的前列腺组织进行比较。我们的目标是： 1）探测老年小鼠BPH/BOO/LUTS发病机理中NO•-SGC-CGMP信号通路的作用 接受cinaciguat治疗； 2）研究CYB5R3组织特异性缺失在前列腺或膀胱中的影响 我们的有条件的KO鼠标； 3）确定cinaciguat/pde5i联合疗法是否可以覆盖PDE5 过表达驱动对PDE5IS的折射率以及任何可能发生的不良心血管效应 cinaciguat。