Abstract 6144: Reduced Number and Function of Endothelial Progenitor Cells in Patients with Aortic Valve Stenosis - A Novel Concept for Valvular Endothelial Cell Repair-
Endothelial destruction and calcification primarily occurs at the aortic side of the degenerative aortic valve (AV). Recent studies suggest that under normal physiological conditions the endothelial cell (EC) layer is kept intact after injury either by division of mature ECs or by restoration with circulating endothelial progenitor cells (EPCs). Thus, a reduced capacity of valvular EC regeneration on the aortic valve due to EC senescence (a non-dividing state) or reduced levels of EPCs may lead to aortic valve stenosis (AS). This study investigated whether the presence of valvular EC senescence and a reduction in the levels of EPCs are associated with degenerative AS. 15 patients with severe AS and 18 age-matched control subjects were included into this study. Explanted calcified AVs were examined for senescence-associtated β-gal staining and immunohistochemistry (IHC) for CD31 and KLF-2. The amount and functional capacity of EPCs were assessed by FACS analysis or migration assay. The expression of telomere repeating factor-2 (TRF-2) was quantified by western blot and the caspase-3 activity was also measured biochemically. IHC showed less KLF-2 expression associated with valvular EC destruction at the aortic side as compared to the ventricular side, suggesting an involvement of turbulent flow in the destruction of EC layer at the aortic side. Furthermore, senescence-associated β-gal activity was mostly localized on the valve endothelium and highly coincided with the calcified lesion at the aortic side. The number (9.3±1.5 vs. 20.5±1.7 cells per 106 mononuclear cells; p<0.01) and the migratory capacity (107.8±14.1 vs. 185.0±16.2 cells per 1000 cells; p<0.01) of EPCs were significantly reduced in AS when compared to control. Caspase-3 activity was significantly increased, whereas the TRF-2 expression was significantly reduced in EPCs isolated from AS when compared to control. This study reports for the first time the reduced regenerative capacity of valvular ECs due to senescence and decreased levels of EPCs related to “biological” aging in patients with AS. These data may offer a novel pathophysiological concept for impaired endogenous valve repair, leading to progression of age-associated AV disease.