Phosphodiesterase (PDE) 5 inhibitors sildenafil, tadalafil and vardenafil impact cAMP-specific PDE8 isoforms-linked second messengers and steroid production in a mouse Leydig tumor cell line

被引：12

作者：

Limoncella, Silvia ^{[1
]}

Lazzaretti, Clara ^{[1
,2
]}

Paradiso, Elia ^{[1
,2
]}

D'Alessandro, Sara ^{[1
,2
]}

Barbagallo, Federica ^{[3
]}

Pacifico, Salvatore ^{[4
]}

Guerrini, Remo ^{[4
]}

Tagliavini, Simonetta ^{[5
]}

Trenti, Tommaso ^{[5
]}

Santi, Daniele ^{[1
,6
]}

Simoni, Manuela ^{[1
,6
,7
]}

Sola, Marco ^{[8
]}

Di Rocco, Giulia ^{[8
]}

Casarini, Livio ^{[1
,7
]}

机构：

[1] Univ Modena & Reggio Emilia, Dept Biomed Metab & Neural Sci, Unit Endocrinol, Modena, Italy

[2] Univ Modena & Reggio Emilia, Int PhD Sch Clin & Expt Med CEM, Modena, Italy

[3] Sapienza Univ, Dept Expt Med, Rome, Italy

[4] Univ Ferrara, Dept Chem Pharmaceut & Agr Sci, Ferrara, Italy

[5] Azienda USL Modena, Dept Lab Med & Pathol Anat, Modena, Italy

[6] Azienda Osped Univ Modena, Unit Endocrinol, Dept Med Specialties, Modena, Italy

[7] Univ Modena & Reggio Emilia, Ctr Genom Res, Modena, Italy

[8] Univ Modena & Reggio Emilia, Dept Life Sci, Via G Campi 297, I-41125 Modena, Italy

来源：

MOLECULAR AND CELLULAR ENDOCRINOLOGY | 2022年 / 542卷

关键词：

PDE5i; Vardenafil; Tadalafil; Sildenafil; LH; hCG; IN-VITRO; PROTEIN; PARAMETERS; BINDING; DOMAIN;

D O I：

10.1016/j.mce.2021.111527

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Type 5 phosphodiesterase (PDE5) blockade by inhibitors (PDE5i) results in intracellular cyclic guanosine monophosphate (cGMP) increase and smooth muscle relaxation and are used for the treatment of men erectile dysfunction. Although they have high specificity for PDE5, these inhibitors are suspected to cross-interact also with cyclic adenosine monophosphate (cAMP)-specific PDEs, inducing the intracellular accumulation of this cyclic nucleotide and related testosterone increase, positively impacting male reproductive parameters. However, the link between the use of PDE5i and the activation of cAMP-mediated steroidogenesis is still unclear. We have investigated whether three PDE5i, sildenafil, tadalafil and vardenafil, cross-interacts with the high affinity cAMP-specific enzymes type 8A and 8B PDEs (PDE8A and PDE8B), in live, transfected mouse Leydig tumor (mLTC1) and human embryonic kidney (HEK293) cell lines in vitro. The PDE5i-induced production of cAMPdependent testosterone and its precursor progesterone was evaluated as well. We have developed PDE8A/B biosensors and modified cyclic nucleotides confirming enzyme binding to cAMP, but not to cGMP, in our cell models. cAMP binding to PDE8A/B was displaced upon cell treatment with PDE5i, revealing that sildenafil, tadalafil and vardenafil have similar effectiveness in live cells, in vitro. The cross-interaction between PDE5i and PDE8A/B supports the gonadotropin-enhanced intracellular cAMP increase, occurring together with cGMP increase, as well as steroid synthesis. Indeed, we found that Leydig cell treatment by PDE5i increases progesterone and testosterone production triggered by gonadotropins. We demonstrated that PDE5i may interact with the cAMP-specific PDE8A and PDE8B, possibly inducing intracellular cAMP and sex steroid hormone increase. These findings support clinical data suggesting that PDE5i might increase testosterone levels in men.

引用

页数：9