title: Testosterone induces apoptosis in cardiomyocytes by increasing proapoptotic signaling involving tumor necrosis factor-α and renin angiotensin system.
abstract: Anabolic androgenic steroids lead to cardiac complications and have been shown to exhibit proapoptotic effects in cardiac cells; however, the mechanism involved in those effects is unclear. The aim of this study was to assess whether apoptosis and the activation of caspase-3 (Casp-3) induced by testosterone in high concentrations involves increments in tumor necrosis factor-α (TNF-α) concentrations and angiotensin-converting enzyme (ACE) activity in cardiomyocytes (H9c2) cell cultures. Cardiomyocytes were treated with testosterone (5 × 10(-6) mol/L), doxorubicin (9.2 × 10(-6) mol/L), testosterone + etanercept (Eta; 6.67 × 10(-5) mol/L), testosterone + losartan (Los; 10(-7) mol/L), and testosterone + AC-DEVD-CHO (10(-5) mol/L; Casp-3 inhibitor). Apoptosis was determined by flow cytometry and by the proteolytic activity of Casp-3. We demonstrated that incubation of H9c2 cells for 48 h with testosterone causes the apoptotic death of 60-70% of the cells and co-treatments with Eta, Los, or AC-DEVD-CHO reduced this effect. Testosterone also induces apoptosis (concentration dependent) and increases the proteolytic activity of Casp-3, which were reduced by co-treatments. TNF-α and ACE activities were elevated by testosterone treatment, while co-treatment with Los and Eta reduced these effects. We concluded that an interaction between testosterone, angiotensin II, and TNF-α induced apoptosis and Casp-3 activity in cultured cardiomyocytes, which contributed to the reduced viability of these cells induced by testosterone in toxic concentrations.
authors: Department of Pharmacy, University Vila Velha, Espírito Santo, Brazil.
authors: A M
authors: AM
authors: do Nascimento
authors: Department of Pharmacy, University Vila Velha, Espírito Santo, Brazil.
authors: E M
authors: EM
authors: de Lima
authors: Department of Pharmacy, University Vila Velha, Espírito Santo, Brazil.
authors: G A P
authors: GA
authors: Boëchat
authors: Department of Physiological Sciences, Federal University of Espírito Santo, Espírito Santo, Brazil.
authors: S D S
authors: SD
authors: Meyrelles
authors: Department of Physiological Sciences, Federal University of Espírito Santo, Espírito Santo, Brazil.
authors: N S
authors: NS
authors: Bissoli
authors: Department of Pharmacy, University Vila Velha, Espírito Santo, Brazil.
authors: D
authors: D
authors: Lenz
authors: Department of Pharmacy, University Vila Velha, Espírito Santo, Brazil.
authors: D C
authors: DC
authors: Endringer
authors: Department of Pharmacy, University Vila Velha, Espírito Santo, Brazil tadeu.andrade@uvv.br.
authors: T U
authors: TU
authors: de Andrade
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D013739:Testosterone; D007703:Peptidyl-Dipeptidase A; D053148:Caspase 3
keywords: ACE; Anabolic agents; H9c2; TNF-α; apoptosis; caspase-3