Abstract 1201: Lack of Dehydroepiandrosterone-sulfate (DHEAS) contributes to CD4 T Cell-Induced Endothelial Apoptosis in Perimenopausal Women

Abstract

Background: Postmenopausal women develop atherosclerosis faster and have higher incidence of acute coronary syndromes. Endogenous dehydroepiandrosterone-sulfate (DHEAS) is a major source of estrogen for women after menopause. Low levels of DHEAS is also a known risk factor for coronary atherosclerotic disease in men. However, the causal relationship between DHEAS levels in women and acute coronary syndromes (ACS) is not fully understood. In this study, we examined whether CD4 T cells from perimenopausal women (PMW) with low levels of DHEAS induce endothelial apoptosis that is prone to develop plaque erosion. Methods and Results: Fresh CD4 T cells were isolated from 45 PMW within 5 years after menopause (mean age 53.9 ± 6.0 years) and from 40 women with regular menstruation cycles (NC, mean age 34.0 ± 7.4 years). DHEAS levels in plasma by ELISA correlated negatively with age (R = 0.500, P < 0.02). DHEAS was lower in PMW than in NC (P < 0.0001). Estrogen receptor α (ESR1) and estrogen receptor β (ESR2) mRNA of CD4 T cells in PMW were lower compared to NC by real time PCR (P < 0.05). DHEAS levels correlated significantly with ESR2 transcripts (R = 0.789, P < 0.0001), but not with ESR1. Measurement of fragmentation of DAPI-binding nuclear proteins showed that CD4 T cells from PMW induce significant human umbilical vein endothelial cells (HUVEC) apoptosis compared to those from NC (P<0.0001). DHEAS levels correlated negatively with CD4 T cell-induced HUVEC apoptosis (R = 0.499, P < 0.02). Treatment with 17β-estradiol showed reduction of CD4 T cell-induced apoptosis in PMW. Pure estrogen receptor antagonist ICI 172,780 abolished estrogen protection. Conclusions: Our results showed that the aging marker of DHEAS was lower in perimenopausal women, and that the low levels DHEAS, a endogenous major source of estrogen after menopause, induced CD4 T cell-induced endothelial apoptosis may be associated with ESR2. We concluded that low levels of DHEAS in perimenopausal women can be one factor that contributes to the acceleration of plaque erosion in atherosclerotic plaque and acute coronary syndromes.