Effects of genistein on angiotensin-converting enzyme in rats.
Genistein (4,5,7-trihydroxyisoflavone), a phytoestrogen with selective estrogen receptor modulator properties, has received a great deal of attention over the last few years because of its potentially preventive roles against cardiovascular diseases. However, the precise molecular mechanisms for this modulation are not fully elucidated. In this study, we investigated (both in vivo and in vitro) the relationship between genistein and the changes of angiotensin-converting enzyme (ACE) in rat aortic endothelial cells (RAECs), serum and tissue (aorta). ACE expression was assessed by the immunofluorescence and the reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Serum and tissue ACE activity was detected with a commercial kit. Genistein exhibited a concentration-dependent inhibitory effect on the expression of ACE, particularly at higher concentrations (24.70+/-1.20 at 100microM, P<0.01, and 18.22+/-0.92 at 200microM, P<0.01 compared with the control group 50.49+/-5.19). The estrogen receptor blocker tamoxifen at 100microM attenuated this effect of genistein. The extracellular signal-regulated kinase 1/2 (ERK1/2) blocker PD98059 also markedly inhibited this effect. The observations in vivo were highly consistent with the data in RAECs. These results indicate that genistein inhibits the expression of ACE via estrogen receptor and subsequently ERK1/2 signaling pathway in RAECs. Our results suggest that the down-regulation of ACE with a consequent change in the circulating levels of angiotensin II (Ang II), vasorelaxant angiotensin-(1-7) [Ang-(1-7)] and bradykinin plays an important role in cardiovascular effects of genistein through the ERK1/2 pathway.
Xu
Yin-Yan
YY
Department of Pharmacology, Nanjing Medical University, Nanjing 210029, China.
Yang
Cui
C
Li
Sheng-Nan
SN
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004965:Estrogen Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D019833:Genistein / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology
D004965:Estrogen Antagonists; D005419:Flavonoids; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D019833:Genistein; D048049:Extracellular Signal-Regulated MAP Kinases; D007703:Peptidyl-Dipeptidase A; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one