S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
Institute of Vascular Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Prostate. 2022 Jan;82(1):13-25. doi: 10.1002/pros.24244. Epub 2021 Sep 27.
Androgen deprivation therapy (ADT) is a key treatment modality in the management of prostate cancer (PCa), especially for patients with metastatic disease. Increasing evidences suggest that patients who received ADT have increased incidence of diabetes, myocardial infarction, stroke, and even mortality. It is important to understand the pathophysiological mechanisms on how ADT increases cardiovascular risk and induces cardiovascular events, which would provide important information for potential implementation of preventive measures.
Twenty-six 12-week-old male SD rats were divided into four groups for different types of ADTs including: the bilateral orchidectomy group (Orx), LHRH agonist group (leuprolide), LHRH antagonist group (degarelix), and control group. After treated with drug or adjuvant injection every 3 weeks for 24 weeks, all rats were sacrificed and total blood were collected. Aorta, renal arteries, and kidney were preserved for functional assay, immunohistochemistry, western blot, and quantitative reverse-transcription polymerase chain reaction.
In vascular reactivity assays, aorta, intrarenal, and coronary arteries of all three ADT groups showed endothelial dysfunction. AT1R and related molecules at protein and messenger RNA (mRNA) level were tested, and AT1R pathway was shown to be activated and played a role in endothelial dysfunction. Both ACE and AT1R mRNA levels were doubled in the aorta in the leuprolide group while Orx and degarelix groups showed upregulation of AT1R in the kidney tissues. By immunohistochemistry, our result showed higher expression of AT1R in the intrarenal arteries of leuprolide and degarelix groups. The role of reactive oxygen species in endothelial dysfunction was confirmed by DHE fluorescence, nitrotyrosine overexpression, and upregulation of NOX2 in the different ADT treatment groups.
ADT causes endothelial dysfunction in male rats. GnRH receptor agonist compared to GnRH receptor antagonist, showed more impairment of endothelial function in the aorta and intrarenal arteries. Such change might be associated with upregulation and activation of AngII-AT1R-NOX2 induced oxidative stress in the vasculature. These results help to explain the different cardiovascular risks and outcomes related to different modalities of ADT treatment.
去势治疗（ADT）是前列腺癌（PCa）管理中的一种关键治疗方式，特别是对于转移性疾病患者。越来越多的证据表明，接受 ADT 的患者糖尿病、心肌梗死、中风甚至死亡的发生率增加。了解 ADT 如何增加心血管风险并引发心血管事件的病理生理学机制非常重要，这将为潜在的预防措施提供重要信息。
将 26 只 12 周龄雄性 SD 大鼠分为四组，进行不同类型的 ADT 治疗，包括：双侧睾丸切除术组（Orx）、促黄体激素释放激素激动剂组（亮丙瑞林）、促黄体激素释放激素拮抗剂组（degarelix）和对照组。每组大鼠分别用药物或辅助药物每 3 周注射一次，共 24 周后处死，采集全血。保存主动脉、肾动脉和肾脏用于功能测定、免疫组织化学、Western blot 和定量逆转录聚合酶链反应。
在血管反应性测定中，三种 ADT 组的主动脉、肾内和冠状动脉均出现内皮功能障碍。检测 AT1R 及相关分子的蛋白和信使 RNA（mRNA）水平，发现 AT1R 途径被激活并在内皮功能障碍中发挥作用。亮丙瑞林组主动脉中 ACE 和 AT1R mRNA 水平均增加了一倍，而 Orx 和 degarelix 组肾组织中 AT1R 表达上调。免疫组织化学结果显示，亮丙瑞林和 degarelix 组肾内动脉中 AT1R 表达较高。DHE 荧光、硝基酪氨酸过表达和不同 ADT 治疗组中 NOX2 上调证实了活性氧在内皮功能障碍中的作用。
ADT 导致雄性大鼠内皮功能障碍。与 GnRH 受体拮抗剂相比，GnRH 受体激动剂在主动脉和肾内动脉中对内皮功能的损害更大。这种变化可能与血管中 AngII-AT1R-NOX2 诱导的氧化应激的上调和激活有关。这些结果有助于解释不同 ADT 治疗方式相关的不同心血管风险和结果。
