ESTROGEN INHIBITS ENDOTHELIN-1 PRODUCTION AND C-FOS GENE-EXPRESSION IN RAT AORTA

In order to clarify the mechanism underlying the preventive effect of estrogen on atherogenesis, we investigated the role of estrogen in the regulation of endothelin-1 (ET-1) production and c-Sos mRNA expressio n, which may contribute to atherogenesis. Plasma ET-1 concentration in ovariectomized rats (OVX) was twice as high as that in sham-operated female rats (Sham). Estradiol replacement in OVX rats (OVX + E) decrea sed plasma ET-1 to the level in Sham (Sham, 0.68 +/- 0.14; OVX, 1.32 /- 0.14; OVX + E, 0.85 +/- 0.12 pg/ml). Metabolic clearance rate of ET -1 was similar in these three groups of rats, suggesting that the diff erence in plasma ET-1 was due to production rather than degradation. M easurement of immunoreactive ET-1 in tissue extract and immunohistoche mical examination showed that expression of ET-1 in the aortic smooth muscle cells of OVX was increased. The expression of c-fos mRNA in the aorta was also increased in OVX compared with Sham and OVX + E. Intra venous infusion of ET-1 to Sham induced c-fos expression in the aorta, suggesting the contribution of ET-1 to c-fos expression. Tissue cultu re study revealed that DNA synthesis was increased in the aorta and fe moral artery of OVX. These results suggest that inhibition of ET-1 and c-fos expression is involved in the anti-atherogenic action of estrog en.