Abstract 3752: Mineralocorticoid Receptor Antagonism Prevents Aldosterone Mediated Dysfunction of Human Endothelial Progenitor Cells in Vitro, in Vivo and in Patients
Hyperaldosteronism has been associated with vascular injury. Bone marrow derived endothelial progenitor cells (EPC) play an important role in endothelial repair and vascular homeostasis. We therefore examined the effects of aldosterone and its blockade by the mineralocorticoid receptor (MR) antagonist eplerenone on EPC number and function in vitro, in vivo and a clinical trial. EPCs expressed the MR at the gene and protein level. Aldosterone treatment of human EPC led to a translocation of the MR into the nucleus and impaired multiple cellular functions, such as differentiation, migration, proliferation and incorporation in vascular networks. Impaired EPC function was rescued by pharmacological antagonism or genetic ablation of the MR. Aldosterone increased the intracellular production of reactive oxygen species (ROS), which was attenuated by MR blockade. Aldosterone-mediated increase of ROS was mainly protein kinase A-dependent and resulted in cAMP activation with subsequent impairment of EPC migration. Chronic aldosterone infusion in mice (implanted minipumps, 50mg/kg/d for 14d) impaired EPC functionality and resulted in endothelial dysfunction. MR antagonism prevented those effects. In patients with hyperaldosteronism, EPC displayed reduced migratory potential compared with age-matched healthy controls. Impaired function of EPC from patients with hyperaldosteronism significantly correlated with endothelial dysfunction assessed by peripheral arterial tonometry. Importantly, MR antagonism in patients with hyperaldosteronism improved EPC as well as endothelial function. EPC function is impaired in hyperaldosteronism by increased intracellular ROS production and cAMP activation. Beneficial effects of MR antagonists in cardiovascular disease prevention and therapy especially during hyperaldosteronism may be mediated in part by improved EPC biology.