Abstract 15749: The Estrogen-Estrogen Receptor System in Human Cardiac Stem Cells
Epidemiological studies have shown that heart failure is more prevalent in men than in women and that the female heart has a superior ability to cope with aging. The objective of this work was to establish whether the old female human heart possesses a larger pool of cardiac stem cells (hCSCs) and whether the local estradiol-estrogen receptor system (E2-ER) favors the preservation of hCSCs in this gender. The study included men and women older than 70 years of age. The fraction of Ki-67-positive hCSCs was 1.5-fold greater in the old female heart while the senescent marker p16INK4a was more frequently found in old male hCSCs. As a consequence, a 2-fold larger pool of functionally-competent hCSCs was present in women. Male and female hCSCs were found to possess all the molecular components of the E2-ER system. Comparable quantities of ERα and ERβ were detected in old male and female hCSCs at the mRNA and protein level. Similarly, transcript for aromatase was equally expressed in the two cell groups. However, old female hCSCs synthesized and released 2-fold more E2 than male cells, suggesting that the E2-ER axis is more active in female than in male hCSCs. Following exposure to E2 for 8-48 hours, transcripts for ERα and aromatase increased in female hCSCs, which produced 8.5-fold more estradiol ligand. By Western blotting, E2-activated female hCSCs showed a marked increase in the quantity of nuclear ERα. These changes were not observed in male hCSCs. At baseline, replicating hCSCs were 2-fold higher in female than in male hCSCs and this difference increased with E2 stimulation. At 24-48 hours, ∼48% female hCSCs were BrdU-positive while only 10% male hCSCs were traversing the cell cycle. This finding was consistent with the higher levels of telomerase activity in E2-activated female hCSCs. By employing siRNA strategy, we demonstrated that the positive effect of E2 on hCSC proliferation was dependent on ERα. Inhibition of ERα led to marked attenuation of cell replication following E2 stimulation. Opposite effects were seen when ERβ was downregulated. Thus, the local estrogen system favors the maintenance of a pool of functionally-competent hCSCs in the old female heart, preserving the youth of the organ and opposing the onset of a senescent cardiomyopathy.
- © 2011 by American Heart Association, Inc.