Abstract 3492: Nerve Growth Factor Exerts Protective and Regenerative Actions on the Post-Infarct Heart
We showed that nerve growth factor (NGF) promotes angiogenesis and survival of endothelial cells (ECs) and cardiomyocytes (CMs). Here, we investigated whether:
NGF and its receptor trkA are expressed in human infarcted heart;
endogenous NGF mediates spontaneous angiogenesis response to myocardial infarction (MI) in mice;
NGF gene transfer promotes vascular regeneration and cardiac progenitor cells (CPCs) expansion in infarcted heart;
NGF overexpression preserves left ventricular (LV) function.
Immunohistochemistry (IHC) of human heart showed that NGF is highly expressed in CMs of border zone, with signal fading from peri-infarct to remote zone. TrkA was detected in CMs and ECs. To verify the relevance of expressional changes, MI was induced in mice, which then received a NGF neutralizing antibody (Ab-NGF, 3mg/Kg BW, IP every 5d) or control IgG. To study the therapeutic potential of NGF over-expression, Ad.NGF (108 p.f.u.) or Ad.Null were delivered to the peri-infarct zone. Analyses at 2 wks post-MI indicated that Ab-NGF reduces capillary density (P<0.05 vs. IgG) and increases EC and CM apoptosis (TUNEL, P<0.05 for both comparisons vs. IgG). Conversely, Ad.NGF increased capillary density (P<0.05 vs. Ad.Null) and prevented EC and CM apoptosis (P<0.05 for both comparisons vs. Ad.Null). Measurement of LV function by Millar mikrotip catheter showed a significant reduction in LV systolic pressure (LVSP), dP/dtmax and dP/dtmin in Ab-NGF treated mice (P<0.05 for all comparisons vs. IgG). In contrast, Ad.NGF improved indices of LV function (P<0.05 for all comparisons vs. IgG). Moreover, echocardiography (Visualsonics Vevo) showed improved ejection fraction (137%) and fractional shortening (148%) in Ad.NGF mice (P<0.05 for both comparisons vs. Ad.Null). Finally, using flow cytometry and fluorescent counting beads for standardization, the number of Linnegckitpos CPCs per mg of enzymatically digested LV myocardium (3d post-MI) was found increased in Ad.NGF hearts (P<0.05 vs. Ad.Null). The increase in CPCs by Ad.NGF was confirmed by IHC and confocal microscopy. In conclusion, NGF promotes neovascularization, myocardial cell survival, and expansion of CPCs in the infarcted heart, leading to significant preservation of contractile function.