CXCR4 Improves Cardiac Remodeling and Neovascularization, and Regulated Inflammatory and Progenitor Stem Cell Mobilization Post-Myocardial Infarction

Abstract

Recent findings report the potential for bone marrow- (BM) derived hematopoetic stem and progenitor cell mobilization and differentiation in cardiac repair post-myocardial infarction (MI). Following myocardial ischemia, various cytokines/chemokines are produced, including TNFα, SCF, MMP9, and SDF1, all of which stimulate the mobilization and homing of BM-derived cells to the site of injury. Homozygous cxcr4-/- mice are lethal at E18.5 and have a ventricular septal defect. Thus, we compared functional repair in heterozygous CXCR4 knockout mice (cxcr4+/-) to wild-type (WT) mice (cxcr4+/+) to determine the role of CXCR4 receptor in left-ventricular (LV) remodeling post-MI. Evaluation of in vivo LV pressure-volume performance and pathology 5 weeks post-MI showed a worsening of heart function and greater left ventricular dilatation post-MI in cxcr4+/- mice compared to cxcr4+/+. LV end-systolic and diastolic volume (ESV and EDV; μl) increased in cxcr4+/- mice compared to cxcr4+/+ (ESV: 53.63 ± 2.05 vs. 39.12 ± 2.23; p<0.001 and EDV: 59.13 ± 1.89 vs. 49.27 ± 2.27; p<0.001), whereas the LV end-systolic pressure (ESP; mmHg), and percent ejection fraction (EF; %) was decreased in cxcr4+/- mice (ESP: 75.95 ± 3.76 vs. 86.31 ± 2.30; p<0.05 and EF: 12.49 ± 1.78 vs. 24.53 ± 2.01; p<0.001). Pathological evaluation demonstrated a greater infarct size and thinner LV in CXCR4 knockout mice. Immunostaining determined a significantly greater number of vessels in cxcr4+/+ mice compared to the haploid deficient group (26.2 ± 1.07 vs. 15.7 ± 1.07; p<0.001). Staining for infiltrating cells illustrated a significant increase of CD45+MMP9+ as well as dendritic cells mobilization in the cxcr4+/- mice, while cxcr4+/+ mice demonstrated a significantly greater level of SCA1+CD34+ progenitor cell mobilization. These findings show the importance of CXCR4 receptor for cardiac remodeling and neovascularization, as well as regulation of inflammatory and progenitor stem cell mobilization post-MI. Hence, the SDF1-CXCR4 signaling pathway plays a crucial protective role in remodeling and neovascularization post-MI.