Caspase Signaling in ED Patients and Animal Models.
Caspase Signaling in ED Patients and Animal Models.
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ED患者和动物模型中的caspase信号传导。
DOI：
10.1016/j.jsxm.2021.01.175
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Podlasek CA
中科院分区：
文献类型：
--
作者：
Martin S;Harrington DA;Ohlander S;Stupp SI;McVary KT;Podlasek CA
目前治疗勃起功能障碍 (ED) 的方法对前列腺切除术和糖尿病患者无效，因为海绵神经 (CN) 损伤会导致平滑肌细胞凋亡、阴茎重塑和 ED。细胞凋亡可通过内在途径（caspase 9）或外在途径（caspase 8）发生。我们研究了 ED 患者和 CN 损伤大鼠模型中细胞凋亡发生的机制，以确定治疗开发的干预点。对佩罗尼氏症、前列腺切除术和糖尿病 ED 患者 (n=33) 的海绵体组织、接受 CN 挤压的成年 Sprague Dawley 大鼠 (n=24)、BB/WOR 糖尿病大鼠和对照大鼠 (n=8) 以及老年大鼠的阴茎进行 caspase 3 裂解、-8 和 -9（前体和活性形式）的免疫组织化学和蛋白质印迹分析 (n=9)。在佩罗尼氏症患者的海绵体中观察到 Caspase 3 裂解，并且在前列腺切除术和糖尿病组织中丰度更高。 ED 患者阴茎组织中的细胞凋亡主要通过外源性（半胱天冬酶 8）途径发生。在 CN 压碎的大鼠中，损伤后 1-9 天，Caspase 3 裂解丰富，细胞凋亡主要通过内在（Caspase 9）途径发生。 Caspase 9 首次在被膜下的一层中被观察到并且最丰富，几天后在海绵体窦的内壁和窦之间观察到。最初在大鼠海绵体中观察到 Caspase 8 丰度较低，并且在 CN 损伤后的较晚时间点未观察到。老年和糖尿病大鼠的阴茎主要表现出内在机制，糖尿病大鼠也表现出轻微的外在激活。了解如何以及何时进行干预以最有效地预防细胞凋亡反应，对于开发预防 ED 的药物、海绵体形态重塑以及疾病管理至关重要。动物模型可能与 ED 患者观察到的信号机制有所不同。虽然大鼠主要利用 caspase 9，但早期存在通过 caspase 8 的显着通量，只要考虑 CN 损伤后细胞凋亡的时间，这使其成为一个合理的模型。在 ED 患者中，细胞凋亡主要通过外源性 caspase 8 依赖性途径发生，在常用的 CN 挤压 ED 模型中，细胞凋亡主要通过内在性 caspase 9 依赖性途径发生。这是研究设计和解释的一个重要考虑因素，在治疗开发和药物测试中必须考虑到这一点，并且我们的治疗目标理想情况下应该抑制这两种细胞凋亡机制。
Current treatments for erectile dysfunction (ED) are ineffective in prostatectomy and diabetic patients due to cavernous nerve (CN) injury, which causes smooth muscle apoptosis, penile remodeling and ED. Apoptosis can occur via the intrinsic (caspase 9) or extrinsic (caspase 8) pathway. We examined the mechanism of how apoptosis occurs in ED patients and CN injury rat models, to determine points of intervention for therapy development. Immunohistochemical and western analyses for caspase 3-cleaved, −8 and −9 (pro and active forms) were performed in corpora cavernosal tissue from Peyronie’s, prostatectomy and diabetic ED patients (n=33), penis from adult Sprague Dawley rats that underwent CN crush (n=24), BB/WOR diabetic and control rats (n=8), and aged rats (n=9). Caspase 3-cleaved was observed in corpora cavernosa from Peyronie’s patients, and at higher abundance in prostatectomy and diabetic tissues. Apoptosis takes place primarily through the extrinsic (caspase 8) pathway in penis tissue of ED patients. In the CN crushed rat, caspase 3 cleaved was abundant from 1–9 days after injury, and apoptosis takes place primarily via the intrinsic (caspase 9) pathway. Caspase 9 was first observed and most abundant in a layer under the tunica, and after several days was observed in the lining of and between the sinuses of the corpora cavernosa. Caspase 8 was observed initially at low abundance in the rat corpora cavernosa, and was not observed at later time points after CN injury. Aged and diabetic rat penis primarily exhibited intrinsic mechanisms, with diabetic rats also exhibiting mild extrinsic activation. Knowing how and when to intervene to prevent the apoptotic response most effectively, is critical for development of drugs to prevent ED, morphological remodeling of the corpora cavernosa, and thus disease management. Animal models may diverge from the signaling mechanisms observed in ED patients. While the rat utilizes primarily caspase 9, there is significant flux through caspase 8 early on, making it a reasonable model, as long as the timing of apoptosis is considered after CN injury. Apoptosis takes place primarily through the extrinsic caspase 8 dependent pathway in ED patients, and via the intrinsic caspase 9 dependent pathway in commonly used CN crush ED models. This is an important consideration for study design and interpretation that must be taken into account for therapy development and testing of drugs, and our therapeutic targets should ideally inhibit both apoptotic mechanisms.
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影响因子：
1.4
作者：
Atilgan D;Parlaktas BS;Uluocak N;Kolukcu E;Erdemir F;Ozyurt H;Erkorkmaz U
通讯作者：
Erkorkmaz U
影响因子：
6.6
作者：
Klein, LT;Miller, MI;Shabsigh, R
通讯作者：
Shabsigh, R
影响因子：
56.9
作者：
BURNETT, AL;LOWENSTEIN, CJ;SNYDER, SH
通讯作者：
SNYDER, SH
影响因子：
5.3
作者：
Nangle, Matthew R.;Keast, Janet R.
通讯作者：
Keast, Janet R.
影响因子：
3.5
作者：
Ferrer, Julio Eduardo;Velez, Juan Diego;Herrera, Ana Milena
通讯作者：
Herrera, Ana Milena