Abstract 429: The Failing Senescent Heart Contains a Pool of Functionally Competent Progenitor Cells

Abstract

A critical question concerns whether myocardial aging affects uniformly all cardiac progenitor cells (CPCs) or a subset of functionally competent CPCs persists in the senescent heart suggesting that these cells may be activated to form new contracting myocardium. CPCs isolated from the heart of rats at 3, 12, 16 and 24 months were found to express IGF-1-IGF-1R, HGF-c-Met and the components of the renin-angiotensin system (RAS). Although mRNA for angiotensinogen and AT1-receptors decreased in old CPCs, the quantity of these proteins did not vary with aging. Renin mRNA increased at 12 and 16 months and returned to baseline at 24 months. Additionally, Ang II synthesis was 3-fold higher in old than in young CPCs and this difference persisted after ligand activation. Conversely, a decrease in IGF-1R, IGF-1 and HGF mRNA, and IGF-1R and c-Met proteins occurred in old CPCs. Baseline values for IGF-1 secretion were similar in young and old CPCs, but in response to ligand stimulation IGF-1 synthesis was 8-fold higher in young CPCs. HGF did not vary. Collectively, these results indicate that aging led to an increase in RAS function and a decrease in IGF-1-IGF-1R and HGF-c-Met function in CPCs. However, whether these aging effects involved the entire CPC pool remained unknown. Based on the expression of the senescence-associated protein p16 INK4a and telomere length, CPCs in the old heart consisted of two subsets: a large compartment of p16 INK4a -positive CPCs with short telomeres and a small pool of p16 INK4a -negative CPCs with long telomeres. CPCs expressing IGF-1-IGF-1R and HGF-c-Met were consistently negative for p16 INK4a while p16 INK4a was detected in CPCs positive for Ang II and AT1-receptors. Therefore, the ability of IGF-1 and HGF to induce CPC proliferation was attenuated but not abolished in old CPCs which also showed a modest 29% decrease in telomerase activity. Ang II stimulated apoptosis in both young and old CPCs but oxidative DNA damage was higher in old cells. Studies in vivo were then performed documenting that CPCs can be activated in the old heart by the local injection of growth factors. By this strategy, the senescent heart phenotype was partially corrected and the improvement in cardiac hemodynamics resulted in prolongation of maximum lifespan.