Abstract 2715: Decreased Myofibroblast Accumulation Predisposes cKit-Deficient (KitW/KitW-v) Mice to LV Dilatation
Introduction: We tested the hypothesis that the function of the cKit receptor is important to post-myocardial infarction (MI) cardiac remodeling. Since cardiac repair after injury requires myofibroblast proliferation, we speculated that cKit function may impact the myofibroblast response.
Methods: We used the KitW/KitW-vmice that carry mutations in both alleles of the cKit receptor tyrosine kinase and their congenic Kit+/+ littermates to assess the importance of cKit function in cardiac remodeling after MI induced by coronary ligation. Cardiac function (fractional area contraction=FAC; left ventricular end diastolic diameter=LVEDD) and geometry (n=5 per group) were analyzed by echocardiography at 0, 7, 14, and 45 days after MI. At 0, 3, and 7 days post-MI, immunofluorescent staining and flow cytometry using an antibody against smooth muscle actin (SMA) were performed to determine the number of accumulated myofibroblasts. Myofibroblast proliferation was determined using Ki67/SMA double immuno-fluorescent staining.
Results: After MI, cardiac function deteriorated most rapidly in the mutant mice: FAC showed a 0.5-fold reduction in Kit+/+ and a 5.3-fold reduction in KitW/KitW-v (p<0.001). LVEDD increased 1.5-fold in Kit+/+ and 1.9-fold in KitW/KitW-v mice by day 7 (p<0.05). The percentage of proliferating cells in the infarct borderzone was significantly lower in KitW/KitW-v than Kit+/+ mice on days 3 and 7 (p<0.01, and p<0.001, respectively). The percentage of proliferating SMA+ cells was 1.7-fold lower in the mutant mice at day 3 (p<0.01); this resulted in a 1.9-fold reduction in the percentage of SMA+ pixels within the infarct, and a 1.7-fold reduction in the number of SMA+ cells as detected by flow cytometry of whole heart digests (p<0.01).
Conclusion: The myofibroblast response after MI was diminished in the KitW/KitW-v mice, and may explain the lack of scar contracture resulting in cardiac dilatation and ventricular dysfunction in these animals. Interventions that increase the infiltration of cKit cells to the infarcted heart may increase the myofibroblast response to injury, which may in turn enhance scar contracture and improve the recovery of cardiac function after MI.