Simvastatin Treatment Prevents Cell Damage and Regulates Angiogenesis in a Rat Ovarian Torsion and Detorsion Model An Immunohistochemical Study of Caspase-3 and sFlt-1 Expression

Abstract

OBJECTIVE: Ovarian torsion is a condition that affects the development of ovaries and restricts blood flow. It occurs most frequently in women of reproductive age, and delay in torsion resolution may result in necrosis and ovarian loss. Ischemia-reperfusion of ovarian tissue is known to cause oxidative damage. We aimed to investigate caspase-3 expression as it is involved in apoptosis and inflammation, and sFlt-1 which is responsible for endothelial dysfunction produced by various tissues. STUDY DESIGN: Wistar female rats (n=32) were randomly divided into 4 groups: control, ischemia, ischemia-reperfusion, and ischemia-reperfusion +simvastatin. In the control group, the ovaries were surgically opened and closed, then blood and ovarian tissues of the animals were taken. In the ischemia and ischemia-reperfusion groups, the ovaries were surgically opened, and the left ovaries were sealed for ischemia. After 2 hours of ischemia, blood flow was re-allowed for 2.5 hours of reperfusion. In the ischemia-reperfusion group treated with simvastatin (10 mg/kg), rats were given simvastatin orally after reperfusion, and blood and tissue specimens were taken after 3 hours. Malondialdehyde (MDA) levels and glutathione peroxidase (GSH-Px) activities were determined in the ovarian tissue homogenates for each rat. RESULTS: In the simvastatin-administered group, MDA and GSH values decreased as compared to in the ischemia and ischemia-reperfiision groups. In the simvastatin-treated group, GSH values were increased. In the ischemia group, degenerated granular cells in the antral follicle, luteal cells in the corpus luteum, and intense inflammatory cells in the stromal region were positive for expression of caspase-3. In the ischemiareperfusion group, caspase-3 expression was positive in oocyte, granular, and stromal cells. In the ischemia-reperfusion+simvastatin-treated group, caspase-3 expression was negative in the granular cells of the antral follicle. It was positive in some stromal cells and corpus luteum cells. In the ischemia-reperfusion group, there was an increase in the expression of sFlt-1 in the luteal cells of the corpus luteum and in the vascular endothelial and inflammatory cells. In the ischemiareperfusion + simvastatin-treated group, follicle cells and cells in the corpus luteum showed decreased sFlt-1 expression, whereas sFlt-1 expression was positive in vascular endothelial cells. CONCLUSION: We suggest that simvastatin administration could prevent cell damage by affecting proapoptosis activation. Simvastatin administration may induce the regulation of angiogenesis.