Testosterone induces apoptosis in cardiomyocytes by increasing proapoptotic signaling involving tumor necrosis factor-[alpha] and renin angiotensin system

• Published in: Human & experimental toxicology 2015-11, Vol.34 (11), p.1139
• Main Authors: do Nascimento, AM, de Lima, EM, Boëchat, GAP, Meyrelles, SDS, Bissoli, NS, Lenz, D, Endringer, DC, de Andrade, TU
• Format: Article
• Language: English
• Subjects: Apoptosis; Cardiomyocytes; Signaling; Testosterone; Toxicology; Tumor necrosis factor-TNF
• ISSN: 0960-3271; 1477-0903
• DOI: 10.1177/0960327115571766

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.