Spatial distribution of nerve sprouting after myocardial infarction in mice

BACKGROUND Myocardial infarction (MI) elicits nerve sprouting. OBJECTIVES The purpose of this study was to determine the spatial distribution of nerve sprouting and neurotrophic gene expression after MI. METHODS We created MI in mice by coronary artery ligation. The hearts were removed 3 hours to 2 months after MI and examined for nerve fiber density and neurotrophic factor gene expression using Affymetrix microarray and mRNA analyses. RESULTS The density of nerve fibers immunopositive for growth-associated protein (GAP)-43 was the highest 3 hours after MI both in the peri-infarct area and in the area remote to infarct, resulting in sympathetic (but not parasympathetic) hyperinnervation in the ventricles. The GAP-43-positive nerve fiber density of myocardium was greater in the outer transverse loop than in the inner vertical loop. The differences between these two myocardial loops peaked within 3 hours after MI and persisted for 2 months afterward. Gene expression of nerve growth factor, insulin-like growth factor, leukemia inhibitory factor, transforming growth factor-beta(3), and interleukin-1 alpha was increased up to 2 months after MI compared with normal control. Expression of these growth factors was more pronounced and persistent in the peri-infarct area than in the remote area. CONCLUSION MI induces sympathetic nerve sprouting in both peri-infarct and remote areas, more in the outer transverse Loop. Selective up-regulation of nerve growth factor, insulin-like growth factor, Leukemia inhibitory factor, transforming growth factor-beta(3), and interleukin-la occurred in the peri-infarct area and, to a Lesser extent, in the remote area.