Estradiol prevents homocysteine-induced endothelial injury in male rats

Objective: We investigated whether estradiol may prevent accelerated atherosclerosis due to hyperhomocysteinemia by enhancing the antioxidant system. Methods: Male Wistar rats were treated with placebo (P) or 1 mg (1E2) and 2 mg (2E2) 17β estradiol. Half of the animals ( n =6) from each group received homocysteine (Hcy, 100 mg/kg/day) administered in the drinking water for 60 days (P/Hcy, 1E2/Hcy and 2E2/Hcy). Glutathione (GSH) content and glucose-6-phosphate dehydrogenase (G6PDH) activity were determined in myocardial tissues, as well as the serum Hcy concentrations and blood levels of hydrogen peroxide (H2O2). The relaxation response of aortic ring segments to acetylcholine (ACh) was used for the assessment of endothelial function, and hematoxylin-eosin stained thin sections of rat aorta were used for detection of the histological changes (namely endothelial damage and wall thickening). Results: Depression of relaxation to ACh occurred in P/Hcy compared to P (15.7±4% vs. 96.3±7%, P <0.0001), but estrogen significantly restored endothelium dependent relaxation in hyperhomocysteinemic rats (86.8±9.3%, P <0.001). Histological examination revealed aortic endothelial denudation in P/Hcy while the endothelial structures of the aorta from the 1E2/Hcy and 2E2/Hcy appeared normal. Significant reductions in GSH and G6PDH levels were detected in P/Hcy (1.5±0.01 μmol/g and 3.21±1.2 U/mg, respectively) compared to 1E2/Hcy (2.5±0.3 μmol/g and 12.81±1.5 U/mg, P <0.001) and 2E2/Hcy (3.11±1.1 μmol/g and 15.66±4 U/mg, P <0.001). In addition, blood H2O2 level in 1E2/Hcy and 2E2/Hcy remained low while it was raised significantly in P/Hcy compared to P ( P <0.001). Conclusions: These data suggest that the observed reduction of GSH levels and suppression of G6PDH activity induced by Hcy coupled, with endothelial ultrastructural changes and impaired function, all reversed by estradiol, may have relevance to the mechanisms of atherogenesis and the beneficial effects of estrogen replacement therapy.