AUTHOR=Álvarez-Maestro Mario , Eguibar Aritz , Chanca Patricia , Klett-Mingo Mercedes , Gómez Rivas Juan , Buño-Soto Antonio , de Bethencourt Fermín R. , Ferrer Mercedes 

TITLE=Androgen Deprivation Therapy in Patients With Prostate Cancer Increases Serum Levels of Thromboxane A2: Cardiovascular Implications

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.653126

DOI=10.3389/fcvm.2021.653126

ISSN=2297-055X

ABSTRACT=Introduction
Androgens have been described as important players in the regulation of vascular function/structure through their action on the release and effect of vasoactive factors, such as prostanoids. Patients with prostate cancer (PCa) under androgen deprivation therapies (ADT) present increased risk of cardiovascular mortality. Since thromboxane A2 (TXA2) is one of the most studied prostanoids and its involvement in different cardiovascular diseases has been described, the aim of this study was to investigate: (i) the effect of ADT on the serum levels of TXA2 in PCa patients and its possible link to the redox status; and (ii) the effect of the non hydrolyzable TXA2 analogue U-46619 on the function of aorta of male rat. 

Methods
The levels of TXA2 and total antioxidant status in 50 healthy subjects, 54 PCa patients and 57 PCa patients under ADT were evaluated. These determinations were accompanied by levels of testosterone, and C-reactive protein as inflammation marker. In aortic segments from male rat the U46619-induced effect on: (i) the vasomotor responses to acetylcholine (ACh), to the NO donor sodium nitroprusside (SNP), to the carbon monoxide releasing molecule-3 (CORM-3) and to noradrenaline (NA) and (ii) the expression of cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1) and phosphorylated ERK1/2 were analyzed. 

Results
The serum level of TXA2 in patients with PCa was increased with respect to healthy subjects, that was further increased by ADT. There was no modification in the total antioxidant status among the three experimental groups. In aortic segments from male rat the TXA2 analogue decreased the endothelium-dependent relaxation and the sensitivity of smooth muscle cells to NO, while increased the vasoconstriction induced by NA; the expression of COX-2, HO-1 and pERK1/2 were also increased.

Conclusions
ADT increased, along with other inflammatory/oxidative markers, the serum levels of TXA2. The fact that TXA2 negatively impact the vascular function and structure of aorta of healthy male rats, suggests that this deleterious effect could be potentiated in pathophysiological conditions. Therefore, inhibition/blockage of TXA2 could be considered a potential strategy to protect the cardiovascular system, particularly in patients under ADT.