Pathway analysis of microarray data from corpora cavernosal tissue of patients with a prostatectomy or Peyronie disease in comparison with a cavernous nerve-injured rat model of erectile dysfunction.
Pathway analysis of microarray data from corpora cavernosal tissue of patients with a prostatectomy or Peyronie disease in comparison with a cavernous nerve-injured rat model of erectile dysfunction.
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DOI：
10.1093/jsxmed/qdac019
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发表时间：
2023-01
期刊：
影响因子：
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通讯作者：
T. Searl;S. Ohlander;K. McVary;C. Podlasek
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文献类型：
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作者：
T. Searl;S. Ohlander;K. McVary;C. Podlasek
简介 接受前列腺切除术的患者发生勃起功能障碍 (ED) 的风险很高，而 5 型磷酸二酯酶抑制剂对勃起功能障碍 (ED) 无效。前列腺切除术期间海绵体神经 (CN) 经常受损，导致阴茎失去神经支配。这会引发海绵体重塑（细胞凋亡和纤维化）并导致 ED。目的 为了帮助开发新型 ED 疗法，当前的目标是全面了解海绵体中的信号传导机制如何随着 CN 神经支配的丧失而改变，从而导致 ED。方法 对前列腺切除术 (n = 3) 或佩罗尼病 (对照，n = 3) 患者的海绵体组织进行微阵列和通路分析。将结果与 Sprague-Dawley 大鼠 CN 损伤模型 (n = 10) 的分析进行比较。 RNA通过TRIzol提取，DNA酶处理，并通过Qiagen Mini Kit纯化。使用人类基因 2.0 ST 阵列和 RU34 大鼠阵列进行微阵列。通过多种分析工具（ShinyGO、Ingenuity、WebGestalt）和数据库（GO、Reactome）鉴定差异表达基因。使用2倍变化作为差异表达的阈值。结果 确定了前列腺切除术患者和大鼠 CN 损伤模型中 CN 损伤所改变（上调或下调）的通路。结果 微阵列从前列腺切除术队列中鉴定出海绵体中 197 个差异表达的蛋白质编码基因，其中 100 个基因上调，97 个基因下调。已确定影响组织形态的信号通路改变包括以下内容：神经系统疾病、细胞死亡和存活、组织和细胞发育、骨骼和肌肉发育和疾病、结缔组织发育和功能、组织形态、胚胎发育、生长和增殖、细胞间信号传导以及细胞功能和维持。这些人类通路与 CN 损伤的大鼠 ED 模型中观察到的通路高度相似。临床意义 在 CN 发生急性手术损伤后很长一段时间内，患者的显着阴茎重塑仍在持续，这为临床干预逆转阴茎重塑和改善勃起功能提供了机会。优点和局限性 了解信号通路如何响应 CN 损伤而变化，以及这些变化如何转化为海绵体形态的改变和随后的 ED，对于确定治疗开发的战略目标至关重要。结论 在前列腺切除术患者的阴茎中，发现了调节组织稳态、形态发生和发育的信号通路发生了改变，并且发现细胞凋亡和增殖/再生的竞争力量在 CN 损伤后竞争建立主导地位。这些途径如何相互作用来调节阴茎组织稳态是一个复杂的过程，需要进一步研究。
INTRODUCTION Patients with a prostatectomy are at high risk of developing erectile dysfunction (ED) that is refractory to phosphodiesterase type 5 inhibitors. The cavernous nerve (CN) is frequently damaged during prostatectomy, causing loss of innervation to the penis. This initiates corpora cavernosal remodeling (apoptosis and fibrosis) and results in ED. AIM To aid in the development of novel ED therapies, the current aim was to obtain a global understanding of how signaling mechanisms alter in the corpora cavernosa with loss of CN innervation that results in ED. METHODS Microarray and pathway analysis were performed on the corpora cavernosal tissue of patients with a prostatectomy (n = 3) or Peyronie disease (control, n = 3). Results were compared with an analysis of a Sprague-Dawley rat CN injury model (n = 10). RNA was extracted by TRIzol, DNase treated, and purified by a Qiagen Mini Kit. Microarray was performed with the Human Gene 2.0 ST Array and the RU34 rat array. Differentially expressed genes were identified through several analytic tools (ShinyGO, Ingenuity, WebGestalt) and databases (GO, Reactome). A 2-fold change was used as the threshold for differential expression. OUTCOMES Pathways that were altered (up- or downregulated) in response to CN injury in the prostatectomy patients and a rat CN injury model were determined. RESULTS Microarray identified 197 differentially expressed protein-coding genes in the corpora cavernosa from the prostatectomy cohort, with 100 genes upregulated and 97 genes downregulated. Altered signaling pathways that were identified that affect tissue morphology included the following: neurologic disease, cell death and survival, tissue and cellular development, skeletal and muscle development and disorders, connective tissue development and function, tissue morphology, embryonic development, growth and proliferation, cell-to-cell signaling, and cell function and maintenance. These human pathways have high similarity to those observed in the CN-injured rat ED model. CLINICAL IMPLICATIONS Significant penile remodeling continues in patients long after the acute surgical injury to the CN takes place, offering the opportunity for clinical intervention to reverse penile remodeling and improve erectile function. STRENGTHS AND LIMITATIONS Understanding how signaling pathways change in response to CN injury and how these changes translate to altered morphology of the corpora cavernosa and ensuing ED is critical to identify strategic targets for therapy development. CONCLUSION Altered signaling in pathways that regulate tissue homeostasis, morphogenesis, and development was identified in penes of patients with a prostatectomy, and competitive forces of apoptosis and proliferation/regeneration were found to compete to establish dominance after CN injury. How these pathways interact to regulate penis tissue homeostasis is a complex process that requires further investigation.