Homocysteine-induced caspase-3 activation by endoplasmic reticulum stress in endothelial progenitor cells from patients with coronary heart disease and healthy donors

Abstract

Previous studies have suggested an association of hyperhomocysteinemia- induced vascular pathology with enhanced apoptotic potential of endothelial progenitor cells in patients with coronary heart disease. Our results indicate that 500μmol/L homocysteine induced endothelial progenitor cell apoptosis and activation of caspase-3, both of which were abolished by 100μmol/L and 200μmol/L salubrinal, an agent that prevents endoplasmicreticulum stress-induced apoptosis. The addition of 500μmol/L homocysteine caused a release of Ca 2+ from intracellular stores, and enhanced phosphor-eukaryotic initiation factor 2α phosphorylation at Ser51 and the expression of a glucose-regulatedprotein of 78 kDa and a C/EBP homologous protein independently of extracellular Ca 2+. These effects of homocysteine on endothelial progenitor cells were significantly greater inpatients with coronary heart disease than in healthy donors. These findings suggest that homocysteine induces endoplasmic reticulum stress-mediated activation of caspase-3 in endothelial progenitor cells, an event that is enhanced in patients with coronary heart disease. Furthermore, enhanced endoplasmic reticulum stress-mediated activation of caspase-3 in endothelial progenitor cells might be involved in hyperhomocysteinemia-associated vascular pathology.