Effects of Oral Estrogen on Aortic ROS-Generating and -Scavenging Enzymes and Atherosclerosis in apoE-Deficient Mice

The effect of hormone replacement therapy (HRT) on cardiovascular diseases remains controversial. Studies conducted on postmenopausal women indicate that oral HRT increases risk factors that may counteract the atheroprotective effect of estrogen. However, the effects of estrogen on atherosclerosis have been examined using subcutaneous estrogen in most animal studies, which points to the need for evaluating the effect of oral estrogen. Reactive oxygen species (ROS) have emerged as critical factors in the pathogenesis of atherosclerosis. This study examined the effect of long-term oral estrogen treatment on aortic oxidative stress and atherosclerosis in female apoE(-/-) mice to mimic HRT in humans. Ovariectomized apoE(-/-) mice were given 6 mu g/day of oral 17 beta-estradiol (E-2) or control vehicle for 12 weeks. Estrogen treatment reduced atherosclerotic lesions by 38% (E-2: 0.20 +/- 0.01 mm(2)/section; control vehicle: 0.32 +/- 0.02 mm(2)/section) and intima by 32% (E-2: 0.44 +/- 0.02 mm(2)/section; control vehicle: 0.65 +/- 0.04 mm(2)/section) in the aortic root. Serum levels of total and low-density lipoprotein cholesterol were significantly decreased after estrogen treatment. Aortic superoxide anion levels and the expression of NAD(P)H oxidase subunit p22(phox) markedly decreased, and two ROS scavenging enzymes, Cu/ZnSOD and MnSOD, were upregulated after estrogen treatment. Estrogen at physiological concentration inhibited tumor necrosis factor-alpha-stimulated NAD(P)H oxidase activity in both cultured smooth muscle cells and peritoneal macrophages. These results showed that long-term oral estrogen treatment reduces ROS levels and atherosclerosis progression in apoE(-/-) mice. Oral estrogen alters ROS-generating and -scavenging enzyme expression, suggesting that anti-oxidative actions in the vessel wall contribute to atheroprotective effects of estrogen. Exp Biol Med 234:1037-1046, 2009