Abstract 254: Defects in c-kit Receptor Function Affect Myocyte Turnover Resulting in Premature Myocardial Aging in the W/WV Mouse
The objective of this study was to determine whether attenuation of cardiac stem cell (CSC) growth in the adult heart interferes with physiologic cell turnover leading to premature accumulation of senescent myocytes and myocardial aging. For this purpose, W/WV mice, which carry a mutated non-functional c-kit receptor, were studied. The W/WV mouse is a compound heterozygous mutant mouse. The W mutation corresponds to a large amino acid deletion that includes the transmembrane domain of the c-kit receptor while the WV mutation is a point mutation in the kinase domain of this receptor. These genetic modifications reduce c-kit kinase activity by approximately 80-90% affecting hematopoiesis, gametogenesis and melanogenesis. Echocardiographically, at 2-3 months of age, LV diameters and ejection fraction were similar in controls and W/WV mice. However, at 5-6 months and 8-9 months, diastolic and systolic LVDs were larger in W/WV mice than in WT. Ejection fraction decreased with age in W/WV mice. These various aspects of negative ventricular remodeling typically occur with the development of the aging myopathy in mice 24 month-old and older. Moreover, ventricular dilation is commonly associated with wall thinning, both critical parameters of diastolic and systolic wall stress. Importantly, these anatomical and functional changes in W/WV mice were associated with a marked increase in the percentage of CSCs and myocytes expressing the senescence-associated marker p16INK4a. At two months of age, wild-type mice and W/WV mice had the same number of LV myocytes which were essentially identical in volume. However, in comparison with wild-type mice, W/WV mice at 4 months of age had a decreased number of LV myocytes which were larger in volume. The magnitude of myocyte proliferation at the time of sacrifice was assessed by two markers of the cell cycle, Ki67 and MCM5. On average, cycling myocytes were 3-4-fold higher in wild type mice than in W/WV mice. In contrast, apoptotic myocytes, evaluated by the TdT assay and hairpin 1 in situ ligation, were significantly more frequent in W/WV mice than in WT mice. In conclusion, mutation of the c-kit receptor in CSCs impairs new myocyte formation and promotes accumulation of senescent myocytes.
- © 2013 by American Heart Association, Inc.