Reduction of oxidative stress and AT1 receptor expression by the selective oestrogen receptor modulator idoxifene.
1. The beneficial vasoprotective effects of oestrogens are hampered by their side effects on secondary sexual organs. Selective oestrogen receptor modulators (SERM) such as idoxifene may exert beneficial vascular effects without 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 oxygen species as well as AT1 receptor expression in vascular smooth muscle cells (VSMC). 3. Idoxifene caused a concentration- and time-dependent down-regulation of AT1 receptor mRNA expression, as assessed by Northern analysis. The maximal effect was reached with 10 micromol l(-1) idoxifene after a 4 h incubation period (33+/-7% of control levels). Western blots showed a similar down-regulation of AT1 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 cell 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 AT1 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-dependent pathways. 6. In conclusion, idoxifene reduces angiotensin II-evoked oxidative stress in VSMC. This could in part be explained by idoxifene-induced down-regulation of AT1 receptor expression. These results demonstrate that the selective oestrogen receptor modulator idoxifene may exert beneficial vascular effects which could be useful for therapeutic regimen in postmenopausal women at risk for cardiovascular diseases.
Bäumer
A T
AT
Klinik III für Innere Medizin, Universität zu Köln, Joseph-Stelzmann-Str. 9, 50924 Köln, Germany.
Wassmann
S
S
Ahlbory
K
K
Strehlow
K
K
Müller
C
C
Sauer
H
H
Böhm
M
M
Nickenig
G
G
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013629:Tamoxifen; C071362:idoxifene