Effect of testosterone supplementation on nitroso‐redox imbalance, cardiac metabolism markers, and S100 proteins expression in the heart of castrated male rats

Abstract

The aim of this study was to investigate the effects of castration and testosterone supplementation on nitroso-redox status, cardiac metabolism markers, and S100 proteins expression in the heart of male rats. 50 male Wistar rats were randomized into five groups with ten animals each: group 1: control intact (CON); group 2: sham operated (Sh-O); group 3: sesame oil-treated rats (S-oil); group 4: gonadoectomized (GDX); and group 5: gonadoectomized rats treated with testosterone (GDX-T) for 8 weeks. Our results showed myofibrillar weaving, apoptosis, inflammation, and fibrosis (as reflected by increased activity of MMP 9 and MMP 2) in the heart of gonadoectomized rats. Testosterone supplementation restored the normal structure of the heart. In addition, a state of nitroso-redox imbalance was observed in the heart of castrated rats with increased NO (425.1 ± 322.8 vs. 208 ± 67.06, p ˂ 0.05) and MDA (33.18 ± 9.45 vs. 22.04 ± 7.13, p ˂ 0.05) and decreased GSH levels (0.71 ± 0.13 vs. 1.09 ± 0.19, p = 0.001). Testosterone treatment leads to a re-establish of only NO levels (425.1 ± 322.8 vs. 210.4 ± 114.3, p > 0.05). Markers of cardiac metabolism showed an enhancement of LDH activity (12725 ± 4604 vs. 5381 ± 3122, p ˂ 0.05) in the heart of castrated rats. This was inversed by testosterone replacement (12725 ± 4604 vs. 5781 ± 5187, p ˂ 0.05). Furthermore, castration induced heart's accumulation of triglycerides (37.24 ± 6.17 vs. 27.88 ± 6.47, p ˂ 0.05) and total cholesterol (61.44 ± 3.59 vs. 54.11 ± 7.55, p ˂ 0.05), which were significantly reduced by testosterone supplementation (29.03 ± 2.47 vs. 37.24 ± 6.17, p ˂ 0.05) and (47.9 ± 4.15 vs. 61.44 ± 3.59, p ˂ 0.001). Cardiomyocytes of castrated rats showed a decreased immunoexpression of S100 proteins compared to control animals. A restoration of S100 proteins immunostaining in cardiomyocyte cytoplasm was observed after testosterone supplementation. These findings confirm the deleterious effects of testosterone deficiency on cardiac function and highlight the involvement of nitric oxide, metalloproteinases 2 and 9, and S100 proteins.

Effects of chronic inhibition of Testosterone metabolism on cardiac remodeling after ischemia/reperfusion-induced myocardial damage in gonadectomized rats

“…These observations suggest that DHT is responsible for the detrimental effects on cardiac function/morphology induced by testosterone. This is in agreement with our previous reports showing DHT as an inductor of myocardial damage (Regouat et al, 2018).…”

“…Interestingly, the role of these enzymes' activities in the absence (as in gonadectomized animals) or in states of decreased circulating testosterone is poorly understood. We showed that ORX rats had a significant increase in 5α-reductase expression without changes in aromatase expression, our results suggested a cross-modulation of the activities of these enzymes since inhibition of their activities induced divergent effects in acute I/R-induced myocardial damage (Regouat et al, 2018).…”

“…On the other hand, in general, the heart is considered only a testosterone target tissue, meaning that circulating testosterone that originated in gonads needs to reach and interact with androgenic receptors at the myocardial level in order to induce its effects; however, this does not seem to be the main/only phenomena since at the myocardial level testosterone can be converted into DHT or estradiol by the competing enzymes 5α-reductase and aromatase, respectively (Regouat et al, 2018). Interestingly, the role of these enzymes' activities in the absence (as in gonadectomized animals) or in states of decreased circulating testosterone is poorly understood.…”

“…We had shown that administration of testosterone 15 min prior to reperfusion induced no changes in ischemia/reperfusion-induced (I/R) myocardial damage (after 4 h of reperfusion) in intact male rats, meanwhile, its administration protects the myocardium against ischemia/reperfusion damage in gonadectomized rats (Rubio-Gayosso et al, 2013). It also has been shown that testosterone supplementation in gonadectomized rats improved oxidative stress and decreased triglyceride accumulation (Regouat et al, 2018).…”

Effect of testosterone on the mRNA expression of Wnt-2 and dickkopf1 (DKK1), collagen deposition and oxidative stress in the cardiac tissue in male rats

“…In spite of our findings, one study showed that castration of male rats reduced the contractility of isolated myocytes and increased the accumulation of collagen fibers around blood vessels in the heart. Also, the percentage of fibrotic tissue in the heart of these animals was high (48). It seems that their findings are in spite of our findings.…”