17 -Estradiol but not the phytoestrogen naringenin attenuates aortic cholesterol accumulation in WHHL rabbits

The effects of 17 -estradiol (17 -E 2 ) or the phytoestrogen naringenin on spontaneous atherosclerosis were studied in 36 ovariectomized homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits receiving a semisynthetic control diet; this diet added 0.0040% 17 -E 2; or 0.20% naringenin, for 16 weeks. The uterine weight was increased ( P 0.001) and the concentration of estrogen receptor was decreased ( P 0.001) in the 17 -E 2 group compared with the controls. Total plasma cholesterol and triglycerides were not different from those in the controls. In lipoproteins, HDL cholesterol was increased ( P 0.01), and LDL triglyceride and IDL triglyceride were lowered ( P 0.05). The oxidation (as concentration of malondialdehyde) was increased in LDL ( P 0.05) but not in plasma. The cholesterol accumulation was decreased ( P 0.05) in the ascending aorta and in the total aorta but the ratio of intima to media and area of intima in ascending, thoracic, and abdominal aorta were not significantly different. In the naringenin group the only differences, compared with the control group, were increased HDL cholesterol ( P 0.001) and decreased activity of glutathione reductase ( P 0.05). In conclusion, 17 -E 2 , but not naringenin, attenuated aortic cholesterol accumulation independently of plasma and LDL cholesterol. Further, these results support previously suggested pro-oxidant ability of 17 -E 2 toward LDL and a possible connection between the pro-oxidant nature of 17 -E 2 and its antiatherogenic effect.— Mortensen, A., V. Breinholt, T. Dalsgaard, H. Frandsen, S. T. Lauridsen, J. Laigaard, B. Ottesen, and J-J. Larsen. 17 -Estradiol but not the phytoestrogen naringenin attenuates aortic cholesterol accumulation in WHHL rabbits. J. Lipid Res. 2001. 42: 834–843. Supplementary key words hormone • lipids • atherosclerosis Atherosclerotic cardiovascular disease is the most common cause of death in both men and women in Western societies. The fact that the risk of cardiovascular disease is similar in men and postmenopausal women, and that cardiovascular disease is less prevalent in premenopausal women and women receiving estrogen replacement therapy than in postmenopausal women, suggests a protective effect of estrogens. Indeed, antiatherogenic properties of 17 -estradiol (17 -E 2 ) have been demonstrated in several animal models (1–6). Furthermore, some human data indicate an antiatherogenic effect of 17 -E 2 (7, 8). Dietary flavonoids, present in a number of edible plants, are currently attracting considerable attention because of their estrogenic and antioxidant properties. They are members of a large flavonoid family that shares with steroidal estrogens the ability to bind to the estrogen receptor and to mediate transcription of estrogen-responsive genes. Flavonoids are believed to be major contributors to the beneficial effect of foods of plant origin on coronary heart disease (CHD). Moreover, epidemiological studies indicate that the intake of dietary flavonoids is significantly inversely associated with mortality from CHD (9– 11). Thus, dietary flavonoids with estrogenic properties (so-called phytoestrogens) could possibly be important for postmenopausal women as a natural supplement, or as an alternative to hormone replacement therapy, in prevention of cardiovascular disease. Consequently, a study was designed to evaluate the effect of 17 -E 2 and the phytoestrogen naringenin ( Fig. 1 ) on development of spontaneous atherosclerosis in ovariectomized female Watanabe heritable hyperlipidemic (WHHL) rabbits. The flavonone naringenin, naturally occurring in citrus fruits, was chosen because it has a relatively high in vitro estrogenic activity compared with other flavonoids (12) and it counts for about 10% of the total estimated human flavonoid intake in Denmark (13). Furthermore, the results from several in vitro studies indicated its antiatherogenic activities [reviewed in ref. (14)], but no information about the posAbbreviations: CHD, coronary heart disease; 17 -E 2 , 17 -estradiol; Er , estrogen receptor ; GPx, glutathione peroxidase; GR, glutathione reductase; GST, glutathione transferase; MDA, malondialdehyde; SOD, superoxide dismutase; UDPGT, UDP-glucuronosyltransferase; WHHL, Watanabe heritable hyperlipidemic. 1 To whom correspondence should be addressed. e-mail: [email protected] by gest, on Jauary 5, 2018 w w w .j.org D ow nladed fom