Abstract 576: Defects in the c-kit-SCF System Have Profound Effects on Myocardial Gene Expression
The recognition that the mouse heart contains a compartment of c-kit-positive cardiac progenitor cells (CPCs) raises questions concerning the role of this primitive cell pool in organ homeostasis and tissue repair. In an attempt to define CPC function in the adult myocardium, two transgenic mouse models characterized by defects in the c-kit receptor or its ligand, stem cell factor (SCF), were studied together with the corresponding wild-type littermates (WT). For this purpose, the ventricular myocardium of W/WV mice which have a spontaneous point mutation of the c-kit receptor in one allele (WV) coupled with an amino acid deletion in the other allele (W) was analyzed in terms of global gene expression and compared with that of the heart of WT. Similarly, the myocardium of Sl/Sld mice which have a complete deletion of the SCF gene locus in one allele (Sl) and deletion of the membrane-bound ligand in the other (Sld) was examined at the transcriptional level and differences in gene expression were defined with respect to WT. The myocardium of W/WV mice showed a 1.5-fold or larger mRNA levels for genes implicated in cell proliferation: cyclin D1, cdc2A, c-fos and IGF-1. Conversely, the inhibitor of the cell cycle p21 was 1.5-fold higher in the WT heart. Moreover, typical myocyte hypertrophy genes were upregulated in W/WV: Egr1, Egr3, and Ier5. Importantly, the apoptosis related genes, cell death-inducing DFFA-like effector and the p53-dependent gene Gadd45 were enhanced in W/WV while the redox genes, thioredoxin and glutathione S-transferase α were more apparent in WT myocardium. Comparable changes in gene expression were detected in the myocardium of Sl/Sld mice but they involved a more restricted number of genes. These differences in gene expression may be critical in the reduced ability of W/WV mice to sustain the increased myocardial load induced by aortic banding. In 7 days, aortic stenosis in these mice leads to heart failure and death. In conclusion, a defect in the c-kit-SCF system has profound effects on the expression of genes modulating cell growth and cell death which over time may attenuate the regenerative response of the heart critical for its adaptation to disease states.