Nerve Growth Factor Stimulates Cardiac Regeneration via Cardiomyocyte Proliferation in Experimental Heart Failure

Abstract

Although the adult heart likely retains some regenerative capacity, heart failure (HF) typically remains a progressive disorder. We hypothesise that alterations in the local environment contribute to the failure of regeneration in HF. Previously we showed that nerve growth factor (NGF) is deficient in the failing heart and here we hypothesise that diminished NGF limits the cardiac regenerative response in HF. The capacity of NGF to augment cardiac regeneration was tested in a zebrafish model of HF. Cardiac injury with a HF phenotype was induced in zebrafish larvae at 72 hours post fertilization (hpf) by exposure to aristolochic acid (AA, 2.5 µM, 72–75 hpf). By 168 hpf, AA induced HF and death in 37.5% and 20.8% of larvae respectively (p<0.001). NGF mRNA expression was reduced by 42% (p<0.05). The addition of NGF (50 ng/ml) after exposure to AA reduced the incidence of HF by 50% (p<0.01) and death by 65% (p<0.01). Mechanistically, AA mediated HF was characterised by reduced cardiomyocyte proliferation as reflected by a 6.4 fold decrease in BrdU+ cardiomyocytes (p<0.01) together with features of apoptosis and loss of cardiomyocytes. Following AA exposure, NGF increased the abundance of BrdU+ cardiomyocytes in the heart by 4.8 fold (p<0.05), and this was accompanied by a concomitant significant increase in cardiomyocyte numbers. The proliferative effect of NGF on cardiomyocytes was not associated with an anti-apoptotic effect. Taken together the study suggests that NGF stimulates a regenerative response in the failing zebrafish heart, mediated by stimulation of cardiomyocyte proliferation.

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“…Lockhart et al reported that NGF plays both acute and long-term roles in the regulation of developing sympathetic synapses in the cardiac system (Lockhart et al, 1997). It was previously shown that NGF augments cardiomyocyte proliferation and may play an important role in cardiac regeneration (Lam et al, 2012). Quirici et al explained that low-affinity nerve growth factor receptor (L-NGFR or CD271) defines a subset of cells with high proliferative, clonogenic, and multipotential differentiation ability in adult bone marrow and adipose tissue (Quirici et al, 2002(Quirici et al, , 2010.…”

“…Another study performed by Lam et al indicated that the stimulative regenerative response in failing zebrafish heart of NGF was mediated by stimulation of cardiomyocyte proliferation (Lam et al, 2012). It is thought that NGF increased cardiomyocyte proliferation via inactivating the glycogen synthase kinase-3 beta (GSK-3β) pathway (Lam et al, 2012). Tseng et al reported that the βARs were involved in regulation of neonatal cardiomyocyte proliferation and that this mitogenic control might be mediated via the p70 ribosomal protein S6 kinase (p70 S6K) pathway (Tseng et al, 2001).…”

“…Recently, it was shown that NGF stimulated the angiogenic activity and supported the cardiomyocyte viability in acute myocardial ischemic injury area (Meloni et al, 2010). Another study performed by Lam et al indicated that the stimulative regenerative response in failing zebrafish heart of NGF was mediated by stimulation of cardiomyocyte proliferation (Lam et al, 2012). It is thought that NGF increased cardiomyocyte proliferation via inactivating the glycogen synthase kinase-3 beta (GSK-3β) pathway (Lam et al, 2012).…”

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“…This seminal finding, published in Brain Research in 1977, has triggered the study on neuroimmune connections, leading to today's accumulation of compelling evidence that NGF is wider than the neuron (paraphrasing Emily Dickinson's The brain is wider than the sky). That is, in addition to its neurotrophic function, this talented molecule influences the survival and activity of a large number of "unpredictable", non-neuronal cells such as immune cells, fibroblasts, epithelial cells, pancreatic beta cells, adipose tissue cells, and cardiomyocytes (6,(9)(10)(11)(12)(13)(14)(15). Such non-neuronal actions of NGF, and also of other neurotrophic factors subsequently discovered, open novel avenues in the study of neurobiology, namely, neuroimmunology (8) and, recently, neuroadipology (16).…”

“…Several therapeutic strategies for delivery of NGF in animal models and in human diseases have been explored and clinical steps have been attempted, while others are currently in progress to evaluate whether NGF and/or TrkA receptor agonists can prevent or protect against cell degeneration in the nervous system, visual system, cutaneous and myocardial tissue (14,15,19,(22)(23)(24)(25)(26)(27)(28). It most likely exerts therapeutic effects on cardiometabolic diseases such as atherosclerosis, obesity, type 2 diabetes and metabolic syndrome (29)(30)(31).…”