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

Abstract

<jats:p> 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<jats:sup>−6</jats:sup> mol/L), doxorubicin (9.2 × 10<jats:sup>−6</jats:sup> mol/L), testosterone + etanercept (Eta; 6.67 × 10<jats:sup>−5</jats:sup> mol/L), testosterone + losartan (Los; 10<jats:sup>−7</jats:sup> mol/L), and testosterone + AC-DEVD-CHO (10<jats:sup>−5</jats:sup> 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. </jats:p>

Cardiac myocyte proliferation and maturation near term is inhibited by early gestation maternal testosterone exposure

“…However, given substantially reduced heart weight in early T fetuses but normal cellular dimensions, it is likely that these fetuses have fewer rather than more cardiomyocytes. Testosterone is also known to regulate cardiomyocyte apoptosis, with a prosurvival benefit under conditions of stress with low added levels of testosterone (modeling hormone replacement) (92,93) but proapoptosis with high levels of testosterone (modeling anabolic steroid abuse) (25,62). However, testosterone levels are normal at 135 dGA in fetuses of ewes transiently exposed to excess testosterone earlier in gestation (72).…”

Soy Isoflavones Improve the Spermatogenic Defects in Diet-Induced Obesity Rats through Nrf2/HO-1 Pathway

“…In addition, the number of sperm is positively correlated with testosterone levels. A significant decrease in intratesticular testosterone concentration appears to be an important trigger for apoptosis in spermatogenic epithelial cells [21,22]. In conclusion, male obesity is associated with decreased sperm density and viability, increased sperm DNA damage and changes in reproductive hormones.…”

Protease‐activated receptor‐2 suppresses interleukin (IL)‐10 expression in B cells via upregulating Bcl2L12 in patients with allergic rhinitis

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