Cardiac regeneration: effect of nerve growth factor

摘要: Heart failure (HF) is a leading cause of death, disability and hospitalization particularly in individuals over 65 years age. Current treatments provide symptomatic benefit can also improve survival as well reversing maladaptive ventricular remodelling. However, HF frequently progressively worsens association with the ongoing loss cardiomyocytes. Cardiomyocytes rarely proliferate cardiac progenitor cells (CPCs) are scarce mammalian adult heart. As such, it likely that insufficient regeneration following injury to heart contributes HF. In contrast mammals, zebrafish able robustly regenerate their hearts sufficiently prevent onset Our group has shown key growth factor, Nerve factor (NGF), lowered failing hearts. Therefore, this thesis, I hypothesised investigated whether NGF may have regenerative effect on To address this, cardiotoxic model failure/regeneration was established larval zebrafish. first optimised exposure duration concentration cardiotoxin (aristolochic acid, AA) approximately half exposed develop The addition AA significantly decreased proportion from developing dying prematurely. Conversely, inhibition high affinity (TrkA) receptor increased incidence death. A common feature apoptosis heart, previously an anti-apoptotic role current paradigm hearts, but surprisingly did not attenuate apoptosis. My studies showed induced death by promoting via cardiomyocyte proliferation. total number cardiomyocytes inhibited contrast, proliferation support finding, egg water supplemented Interestingly, isl1 mRNA subsequent treatment compared fish only AA. effects were validated system, using mouse embryonic (E13.5) organ culture model. promoted vitro. addition, transiently upregulated Nrg1 ErbB4 (a known signalling pathway involved proliferation). Also, Isl1 (at developmental stage when Isl1+ CPCs abundant), which suggests might increase cells. This thesis identified novel cardiovascular for NGF. promotes mice, possibly through Nrg1-ErbB4 pathway. deficiency contribute progressive nature due blunted regeneration. Further should therapeutic value