Enalapril inhibits estrogen-induced endometrial hyperplasia in rats through modulation of PPAR-γ/PTEN/PI3K/AKT axis

Endometrial hyperplasia (EH) is a relatively widespread gynecological disorder and some subtypes are considered precancerous lesions. Enalapril (ENP) is an Angiotensin converting enzyme inhibitor with reported antiproliferative activity. This study aimed at evaluating the possible protective effects of ENP against estradiol (E2)-induced EH in rats. ENP was tried at two oral dose levels (3 and 6 mg/kg) against E2 (0.6 mg/kg s.c.). The experiment was continued for 6 successive weeks. Our results demonstrated that ENP significantly ameliorated E2-induced increase in relative weight as well as histopathological alterations. ENP exhibited antioxidant activity by preventing accumulation of lipid peroxidation products and exhaustion of antioxidant enzymes. Further, ENP mitigated E2-induced uterine inflammation as evidenced by preventing the increase in cyclooxygenase-2, interleukin-6 and tumor necrosis factor immuno-expression. ENP displayed pro-apoptotic activity as supported by modification of mRNA expression of Bax and B-cell lymphoma 2 (Bcl-2). Also, ENP inhibited E2-induced decrease in peroxisome proliferator-activated receptor gamma (PPAR-γ) and phosphatase and TENsin homolog (PTEN) immuno-expression as well as the increase in phosphoinositide 3-Kinase (PI3K) phosphorylated protein kinase B (p-AKT) immuno-expression in uterine tissues. In conclusion, ENP prevents E2-induced EH in rats. This can be attributed to its antioxidant, anti-inflammatory and pro-apoptotic activities and modification of PPAR-γ/PTEN/PI3K/AKT axis.