Abstract 890: SCF/C-KIT Compensates for FL/FLT3 Deficiency to Mediate Myocardial Rescue and Repair Post-MI
Inappropriate cardiac remodeling and repair post-myocardial infarction (MI) may lead to heart failure. Studies have reported the importance of stem cell factor ligand (SCF) and its receptor, c-KIT, for the repair of damaged myocardium post-MI. c-KIT is present on a population of lineage negative bone-marrow (BM) derived hematopoetic stem/progenitor cells (HSPCs) and inflammatory cells, such as Natural Killer (NK) cells. It has been demonstrated that through paracrine effects and neovascularization, these BM-derived cells help improve heart function post-injury. However, the precise contribution and activity of c-KIT signaling with other tyrosine kinase receptors in cardiac repair has yet to be defined. In this study, we sought to directly elucidate the connection between c-KIT and FLT3 receptor and their role in myocardial remodeling post-MI. The importance and association of these receptors were demonstrated by subjecting wild type (WT), c-KIT deficient (W/Wv), WT BM transplanted W/Wv (BMT W/Wv), and FLT3 ligand (FL) knockout (flt3l−/−) mice to permanent ligation of the LAD to induce MI. Significantly higher cardiac FL levels were found in the W/Wv mice when compared to BMT W/Wv, in both sham and MI groups (pg/mL/μg: 0.301±0.06 vs. 0.070±0.02 and 0.574±0.12 vs. 0.397±0.05; p<0.05). Similarly, evaluation of SCF revealed a significantly greater level in flt3l−/− mice compared to W/Wv mice post-MI (pg/mL/μg: 7.45±1.0 vs. 3.67±0.7; p<0.05). The inverse association between c-KIT and FLT3 receptors was further demonstrated by the 100% mortality of flt3l−/− mice post-MI when treated with a c-KIT blocker. Evaluation of left ventricular (LV) hemodynamics showed a significantly greater LV end- systolic and diastolic volume (ESV and EDV; μL) in the W/Wv mice when compared to flt3l−/− (ESV: 66.59±3.2 vs. 41.70±3.5; p<0.001 and EDV: 76.36±3.6 vs. 48.01±3.5; p<0.001). These findings demonstrate that compensatory increase in SCF/c-KIT signaling in flt3l−/ − mice post-MI plays a crucial role in reducing ventricular dilation and improving survival. We conclude that c-KIT receptor is essential for myocardial remodeling post-MI.