Reduction of oxidative stress and AT1 receptor expression by the selectiveoestrogen receptor modulator idoxifene

1 The beneficial vasoprotective effects of oestrogens are hampered by their side effects on secondary sexual organs. Selective oestrogen receptor modu lators (SERM) such as idoxifene may exert beneficial vascular effects witho ut influencing cancerogenesis in breast or uterus. 2 In order to investigate vascular effects of selective oestrogen receptor modulators, we examined the impact of idoxifene on production of reactive o xygen species as well as ATI receptor expression in vascular smooth muscle cells (VSMC). 3 Idoxifene caused a concentration- and time-dependent down-regulation of A TI receptor mRNA expression, as assessed by Northern analysis. The maximal effect was reached with 10 mu mol l(-1) idoxifene after a 4 h incubation pe riod (33 +/- 7% of control levels). Western blots showed a similar down-reg ulation of ATI receptor protein to 36 +/- 11% of control levels. 4 Confocal laserscanning microscopy using the redox sensitive marker 2',7'- dichlorofluorescein (DCF) and measurement of NAD(P)H oxidase activity in ce ll homogenates revealed that idoxifene effectively blunted the angiotensin II-induced production of reactive oxygen species. 5 In order to investigate the signal transduction involved in SERM-induced modulation of ATI receptor expression, VSMC were preincubation with PD98059 , genistein, wortmannin, or N-omega-Nitro-L-arginine. The results suggested that idoxifene caused AT1 receptor down-regulation through nitric oxide-de pendent pathways. 6 In conclusion, idoxifene reduces angiotensin II-evoked oxidative stress i n VSMC. This could in part be explained by idoxifene-induced down-regulatio n of AT1 receptor expression. These results demonstrate that the selective oestrogen receptor modulator idoxifene may exert beneficial vascular effect s which could be useful for therapeutic regimen in postmenopausal women at risk for cardiovascular diseases.