Endothelial dysfunction after androgen deprivation therapy and the possible underlying mechanisms

Abstract

Introduction: 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.Methods: 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.Results: 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. Conclusion: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

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“…They may play a role in the endothelial cell function, fat accumulation, and lipid metabolism that may increase the risks of plaque destabilization/acute rupture and CVD in patients receiving LHRH agonists ( 61 – 64 ). One pre-clinical study in male rats demonstrated that LHRH agonists were associated with more impairment of endothelial function in the aorta and intrarenal arteries compared with LHRH antagonists ( 65 ). However, a phase II randomized open-label study revealed that patients with advanced PCa and pre-existing CVD who received LHRH agonists or antagonists for 1 year had no difference in endothelial function.…”

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“…The European Association of Urology guidelines recommend not offering neoadjuvant ADT before surgery for patients with prostate cancer ( MacLennan et al, 2023 ). ADT increased markers of oxidative stress/inflammation and the serum levels of thromboxane A2 (TXA2), which is associated with cardiovascular risk ( Álvarez-Maestro et al, 2021 ) and endothelial dysfunction ( Gilbert et al, 2013 ; Teoh et al, 2022 ), similar to that seen in testosterone deficiency ( Hotta et al, 2019 ; Moreau, 2019 ; Babcock et al, 2022 ).…”

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“…AR and PCa cell redox homeostasis are interconnected, regulating and influencing each other. Currently, ADT can induce oxidative stress damage to PCa cells in addition to targeting AR, leading to therapeutic effects [ 85 , 86 ]. The treatment of PCa cells with ADT results in the induction of endocrine resistance and radiotherapy resistance, as evidenced by an increase in the expression of Nrf2 and antioxidant stress molecules (peroxiredoxin-1, thioredoxin 1, and metallothionein-1) [ 87 ].…”