Abstract 17596: Nerve Growth Factor Promotes Cardiac Regeneration in a Cardiotoxic Model of Heart Failure in Zebrafish
Backgound: Heart failure (HF) typically represents the end result of myocardial damage and myocyte loss. With the recognition that cardiac progenitor cells exist in the heart, there has been considerable interest in the development of strategies for cardiac regeneration in HF. The cardiac surgical resection model in zebrafish (ZF) has been successfully exploited to study myocardial regeneration, however this is not a model of HF and may therefore not account for the influence of potentially important changes in the local environment that could alter the regenerative response. Accordingly we aimed to evaluate the potential for cardiac regeneration in a ZF model of HF and to establish whether this response is modified by factors relevant to HF. In particular we evaluated the role of nerve growth factor (NGF), which is known to be reduced in the failing heart.
Methods and Results: Myocardial damage was induced in 72 hours post fertilization (hpf) ZF larvae, by exposure to aristolochic acid (AA) for 3 hours. By 168hpf, AA induced a HF phenotype and death in 38% and 21% of larvae respectively (p<0.001 vs control). However, in AA exposed ZF treated with NGF (50ng/ml) there was a 50% decrease in the incidence of the HF phenotype (p<0.001) and of death by 65% (p<0.01). Hearts of cmlc2:GFP ZF were also isolated under fluorescence microscopy for real time PCR. AA exposure caused a 1.62 fold increase in caspase3 mRNA expression (p<0.05), consistent with induction of apoptosis. The addition of NGF did not alter caspase expression but increased Islet-1 mRNA levels by 2.7 fold (p<0.05). In association, in ZF incubated in BrdU, whole mount immunohistochemistry revealed that NGF increased the abundance of BrdU in the heart by 2.66 fold (p<0.05), consistent with proliferation of cells in the heart.
Conclusions: In a ZF model of cardiac injury, NGF reduces the incidence of HF and mortality. The effect of NGF is mediated via a regenerative response rather than by a reduction in apoptosis, and this response is accompanied by upregulation of Islet-1.
- © 2010 by American Heart Association, Inc.