17-BETA-ESTRADIOL, ITS METABOLITES, AND PROGESTERONE INHIBIT CARDIAC FIBROBLAST GROWTH

Postmenopausal women (PMW) have increased incidence of cardiovascular disease, and estrogen substitution therapy has been shown to have card ioprotective effects. Since abnormal growth of cardiac fibroblasts (CF s) is associated with hypertension and myocardial infarction and estro gen inhibits vascular smooth muscle cell (SMC) growth, it is feasible that estrogen may attenuate cardiac remodeling by inhibiting CF growth , and this possibility was investigated by using cultured CFs. 17 beta -Estradiol and progesterone, but not 17 alpha-estradiol, estrone, or e striol, inhibited 2.5% FCS-induced proliferation (DNA synthesis and ce ll number) and collagen synthesis (H-3-proline incorporation) in a con centration-dependent manner and to a similar extent in male and female CFs. Compared to 17 beta-estradiol, its metabolites 2-hydroxyestradio l and 2-methoxyestradiol were more potent in inhibiting FCS-induced DN A synthesis, collagen synthesis, and cell proliferation. The inhibitor y effects of 17 beta-estradiol and its metabolites were enhanced in pr esence of progesterone and 4-hydroxytamoxifen (high-affinity estrogen receptor Ligand). Moreover, like estrogens, the dietary phytoestrogens biochanin A and daidzein inhibited FCS-induced growth of CFs. In conc lusion, 17 beta-estradiol, its metabolites, and progesterone inhibit C F growth in a gender-independent fashion. Moreover, hormone replacemen t therapy using 17 beta-estradiol and progesterone may protect PMW aga inst cardiovascular disease by inhibiting CF growth and cardiac remode ling; whereas estrogens that do not inhibit CF growth may be less effe ctive in protecting PMW against cardiovascular disease. Finally, our s tudies provide evidence that phytoestrogens inhibit CF growth and may be clinically useful as a substitute for feminizing estrogens in preve nting cardiovascular disease in both women and men.