Attenuation of Oxidative Stress by Tamoxifen in the Heart of Ovarectomized Rats with Experimentally Induced Hyperthyroidism

Background: Postmenopausal estrogen deficiency increases the incidence of cardiovascular diseases. Although hormone replacement therapy can reduce cardiovascular risk, it is associated with an increased cancer risk. Selective estrogen receptor modulators (SERM), like tamoxifen and related compounds, have mixed estrogen agonistic/antagonistic effects. Tamoxifen may confer significant cardiovascular benefits without the estrogen-associated risks of endometrial and breast cancer. Hyperthyroidism has been recorded as subclinical conditions in postmenopausal women. Increased oxidative stress with high free radical generation has been described previously in animal models of hyperthyroidism. At the present time, the role of iNOS in hyperthyroidism is not clear, and the mechanisms responsible for the elevated NO activity of hyperthyroidism are not completely established. Aim: The present study was designed to investigate the cardioprotective effects of tamoxifen on oxidative damage in heart of ovarectomized rats with experimentally induced hyperthyroidism. Material and Methods: The study was conducted on 40 female albino rats. The experimental animals were divided into five groups, 8 rats each. Group I: Control (sham operated). Group II: Ovarectomized (OVX). Group III: Ovarectomized and hyperthyroid (OVX-HT). Group IV: Ovarectomized and tamoxifen treated (OVX-Tx). Group V: Ovarectomized, hyperthyroid and tamoxifen treated (OVX-HT-Tx). Hyperthyroidism was induced by intraperitoneal administration of L-thyroxine, 25 μ g/100g BW/day for 4 weeks. Tamoxifen was given SC. in a dose of 1mg /kg /day for 4 weeks. Morphometric parameters were evaluated at the end of the 4-week treatment period. The heart weight (mg) to body weight (g) ratio were calculated for evaluation of cardiac hypertrophy. At the end of the experimental period, blood samples and heart of rats were taken for the determination of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels and inducible nitric oxide synthetase (iNOS) gene expression in the heart tissue of studied animals. Thyroxin (T4) levels and serum cholesterol were determined using routine clinical-chemistry methods. Results : The determinant ratio of cardiac hypertrophy the heart mg./body weight g. ratio significantly higher in OVX and OVX-HT rats compared to the control (p=0.02, p<0.01, respectively). This parameter showed insignificant difference between the control and tamoxifen treated groups. Ovariectomy resulted in abnormal elevation of serum cholesterol and heart oxidative stress markers and changes in redox status of the heart tissue. Supplementation of tamoxifen partially alleviated these abnormalities and restored redox homeostasis of heart tissues after ovariectomy. Ovariectomy accompanied with hyperthyroidism also associated with significant increase in oxidative stress parameters. Among the studied oxidation parameters levels of the MDA in OVX rats and those OVX-HT were higher than those of the control groups (p<0.001). Tamoxifen therapy caused a decrease in MDA in the heart tissue of both OVX rats ( p<0.001) and OVX rats with induced hyperthyoidism (p<0.001). In addition, tamoxifen therapy increased heart GSH ( p<0.001) and SOD(p<0.001) in the previous groups. Indeed iNOS was significantly elevated in OVX rats and in OVX with hyperthyroidism, where tamoxifen significantly reduced it partially in both treated groups (IV and V). Conclusion: The study showed the extent of changes in oxidative stress markers in this model of estrogen deficiency with induced hyperthyroidism. The protective effect of tamoxifen against oxidative damage in the heart suggests that tamoxifen as an estrogen modulator plays an important role within the antioxidant defense systems in the heart. The exact molecular mechanisms leading to these findings are not yet completely known. Meanwhile, tamoxifen as an estrogen modulator-therapy opening new avenues for pharmacological prevention of oxidative damage in the heart.