Abstract 5508: PSGL-1-expressing CD4 T Cells Induce Endothelial Injury in Perimenopausal Women with Low Estrogen Levels

Abstract

Background: Atherosclerosis develops rapidly in postmenopausal women, and plaque erosion induces acute coronary syndromes (ACS) in perimenopausal women (PMW). However, the causal relationship between low estrogen levels and the mechanism of plaque erosion in PMW is not fully resolved. We examined whether PWM have historical T cell dysfunction related to adhesion molecules, and whether they experience accelerated plaque erosion as a result. Methods and Results: Fresh CD4 T cells were isolated from 62 PMW (mean age 54.0±5.0 years) and 69 women with regular menstruation cycles (NC, mean age 33.0±8.0 years). Estrogen levels were lower in PMW than in NC (P<0.0001). Measurements of DAPI-binding nuclear protein fragmentations showed that CD4 T cells from PMW induced significant human umbilical vein endothelial cells (HUVEC) apoptosis compared to CD4 T cells from NC (P<0.002). Furthermore, CD4 T cells from PMW had high T cell activation marker CD69 (P<0.001) and expressed strong p-selectin glycoprotein ligand-1(PSGL-1) and integrinβ 2 but not L-selectin and integrin α M by FACS (P<0.0001, P<0.04, respectively). Estrogen levels correlated negatively with PSGL-1 (R=0.448, P<0.02) and integrinβ 2 (R=0.442, P<0.03), and negatively with CD4 T cell-induced HUVEC apoptosis (R=0.524, P<0.03). Rolling and adhesion of CD4 T cells to activated HUVEC under laminar flow showed strong correlation with HUVEC apoptosis (R=0.717, P<0.03 and R=0.562, P<0.03, respectively). Anti-PSGL-1 Ab inhibited both CD4 T cell-rolling and CD4 T cell-adhesion to activated HUVEC (P<0.05, P<0.009, respectively), but anti-CD18 Ab only affected cell-adhesion (P<0.006). Finally, we included anti-PSGL-1 Ab and anti-CD18 Ab in the apoptosis assay due to investigate whether the CD4 T cell-mediated apoptosis of endothelial cells was dependent on PSGL-1. Anti PSGL-1Ab treatment reduced CD4 T cell-induced apoptosis of endothelial cells (P=0.001) while anti integlinβ 2 Ab did not. Conclusions: From these results, we concluded that PSGL-1-expressing CD4 T cells in PMW with low estrogen levels is a factor that contributes to the acceleration of atherosclerosis and plaque erosion.