Repurposing ramipril to mitigate EMT-like transition in endometriosis by PI3K/AKT/S6K1 signalling pathway: a study in...

Endometriosis, an atypical benign disorder, may disrupt epithelial-mesenchymal transition (EMT) due to a dysregulated balance between matrix metalloproteinases (MMPs) and their inhibitors. Ramipril, an angiotensin converting enzyme (ACE) inhibitor, is crucial in mediating angiogenesis, inflammation, oxidative stress, and apoptosis. In the current work, we investigated how ramipril modulates EMT in endometriosis rats. Five adult virgin female Wistar rats were donor rats, and thirty rats were randomly divided into three groups following peritoneal uterine tissue transplantation (group 2 and group 3). The sham control group was group 1. Morphological alterations were predominantly assessed through hematoxylin-eosin (H-E) staining, succeeded by the immunoreactivity analysis of MMP9, tissue inhibitor of metalloproteinases 1 (TIMP1), reversion-inducing cysteine-rich protein with Kazal motifs (RECK), epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), and vimentin in the uteri and ectopic lesions of the specified groups. Zymography was conducted to assess the activities of MMP9 and MMP2. Immunoblotting was subsequently conducted for MMP9, TIMP1, snail, E-cadherin, N-cadherin, and vimentin in both uteri and ectopic lesions. Immunoblotting was conducted for phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mechanistic target of rapamycin (mTOR), p70 ribosomal S6 kinase 1 (S6K1), and hypoxia-inducible factor 1-alpha (HIF-1ɑ) in the ectopic lesions. A significant reduction in the average quantity of ectopic endometrial glands was recorded in group 3. A significant decrease in the expressions of MMP9:TIMP1 (RECK) ratios (p = 0.00012; p = 0.001), snail, p-PI3K, p-AKT, p-mTOR, p-S6K1, and HIF-1ɑ (p < 0.05) proteins was observed in the ectopic lesions of group 3. A significant increase in the E-cadherin to N-cadherin (vimentin) ratios (p = 0.001) was observed in group 3 ectopic lesions. In conclusion, the administration of ramipril led to the reversal of EMT-like process by disrupting the MMP9/PI3K/AKT/S6K1 pathway in rats induced with endometriosis.