Context: In animal models, estrogen inhibits atherogenesis by inhibiting many of the early steps of atherosclerotic plaque formation. However, the lack of cardioprotective effect by postmenopausal hormone replacement therapy (HRT) and possible increase in cardiovascular events observed during the first year after the initiation of HRT, may suggest that once the plaque is formed estrogen may have additional effects that may counteract its beneficial outcomes. Indeed, the effect of estrogen on plaque stability has not been identified.

Objective: We hypothesized that 17-estradiol (E₂) may cause increased apoptosis in human coronary artery endothelial cells (HCAEC). This effect would explain an adverse effect on plaque stability in vivo.

Intervention(s) and Main Outcome Measure(s): The effect of E₂ on apoptosis, cell proliferation, and expression of pro-apoptotic molecules Fas and Fas ligand (FasL) in cultured HCAEC was evaluated.

Results: HCAEC in culture treated with E₂ showed an increase in DNA strand breaks and nuclear fragmentation indicative of apoptosis. E₂ treatment also induced a significant concentration-dependent increase in Fas mRNA and protein expressions in HCAEC. Moreover, the expression of FasL mRNA and secretion of FasL protein by HCAEC were enhanced in response to E₂ treatments.

Conclusions: E₂ increases the apoptosis in cultured HCAEC. Enhanced Fas and FasL expressions in response to E₂ suggests that activation of the Fas/FasL pathway may be a mediator of the pro-apoptotic effects of E₂ in these cells.