Impacto da terapia de privação androgênica com o agonista do receptor do hormônio liberador de gonadotrofinas (Leuprolide) no coração

Abstract

Androgen deprivation therapy (ADT) has been the treatment of choice for prostate cancer (PCa) patients, with gonadotropin-releasing hormone receptor agonists (aGnRHr), such as leuprolide (LP), being an important therapeutic strategy. Despite the survival benefit for PCa patients provided by aGnRHr use, adverse cardiovascular events have been associated with ADT. However, the underlying mechanisms related to this adverse cardiac effect remain poorly understood. The aim of this study is to investigate the cardiac impact of ADT in vivo caused by LP treatment. For this purpose, we used male C57BL/6 mice, 8 to 10 weeks old, which received PBS (control-CTR) or a single injection of LP (110 mg/kg). After 7 days, we performed echocardiography to evaluate cardiac function and ELISA tests to measure plasma levels of testosterone and luteinizing hormone. The heart was removed for gene expression analyses and cardiac immunophenotyping. Cardiomyocytes (CMs) were isolated for morphometric and contractile characterization. mRNA for GnRHr was identified in the heart, and LP treatment induced a reduction in the levels of this transcript. Confirming the efficacy of ADT, plasma testosterone levels decreased in LP-treated animals, while LH levels increased. Functional data measured by echocardiography indicated a reduction in ventricular mass and thickness of the ventricular posterior wall in diastole in LP-treated animals. These findings were confirmed at the cellular level through morphometry, which indicated a reduction in the area, width, and length of ventricular myocytes isolated from LP mice. It was also observed that CMs from LP-treated animals showed an increase in mitochondrial superoxide anion production, confirming the presence of mitochondrial stress. In the same line, CMs from LP-treated mice exhibited a reduction in all contractile parameters, which was also confirmed by measuring the amplitude of the intracellular calcium transient, which was reduced in LP animal cells. LP treatment also reduced cardiac resident macrophages and B lymphocytes, indicating an imbalance in cardiac immune homeostasis. Considering the cardiac effects of testosterone and the fact that its levels are reduced during LP treatment, we subsequently performed orchiectomy (ORX) on mice and investigated the consequences of this reduction for cardiac parameters. Initially, we confirmed the presence of the androgen receptor (AR) in the heart using real-time PCR. Furthermore, it was observed that LP treatment induces an increase in the expression of this receptor. Also, very interestingly, a reduction in the area of CMs from ORX mice was observed, with a decrease in cell width and length. Also similar to what was observed in the LP group, a reduction in contractility was observed in the ORX group compared to SHAM. Together, these data suggest that the reduction in testosterone levels may play a role in the cardiac effects promoted by LP treatment, thus revealing a possible mechanism involved in the adverse effects of androgen deprivation therapy.