Nerve Growth Factor Promotes Cardiac Repair following Myocardial Infarction

Abstract

Rationale: Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated. Objective: To define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI). Key Words: myocardial infarction Ⅲ angiogenesis Ⅲ gene therapy Ⅲ apoptosis M yocardial infarction (MI) remains a major cause of morbidity and mortality and it is responsible for about one third of heart failure cases worldwide. 1 Sudden occlusion of a major coronary artery and acute myocardial ischemia causes rapid death of cardiomyocytes and vascular cells in the area of interest. 2 Loss of cardiomyocytes and vasculature leads to progressive fibrous replacement of myocardium, hypertrophic growth of the spared myocardium, and left ventricular (LV) dilatation. Maladaptive ventricular remodeling contributes to post-MI heart failure, 3 and prognosis of heart failure patients is still poor. 4 Myocardial ischemia triggers a spontaneous angiogenic response aimed at reestablishing myocardial blood flow. Nonetheless, this protective response is usually not sufficient. 5 Nerve growth factor (NGF) is a secreted glycoprotein of the neurotrophin family. NGF elicits its biological effects mainly by binding the high-affinity TrkA receptor (tropomyosin-related receptor A, which is a tyrosine kinase). We and others previously demonstrated that NGF, via TrkA, promotes angiogenesis and endothelial cells (ECs) survival through a mechanism involving the serine/threonine kinase Akt (also known as protein kinase B). 6,7 Akt regulates a variety of cellular functions and it is strongly implicated in angiogenesis and cell survival. 8 We also demonstrated that cultured cardiomyocytes express TrkA and release NGF. 9 Moreover, NGF is an autocrine prosurvival factor for the cardiomyocyte through the Akt/Forkhead box-O transcription factors (Foxo) pathway. 9 Foxo factors stimulate cell death and are downstream targets of Akt. 10 Akt-mediated phosphorylation regulates Foxo-3a subcellular localization and activity: unphosphorylated Foxo-3a resides in the nucleus, whereas Foxo-3a phosphorylation leads to its nuclear exclusion and inactivation. 11 Moreover, Foxo-1 and -3a represses angiogenesis by downregulating endothelial nitric oxide synthase. 12 Experimental evidences suggest that myocardial repair is, at least in part, dependent on c-kit receptor-expressing (c-kit pos ) progenitor cell populations. [13][14][15] Lineage negative Original received October 5, 2009; revision received February 19, 2010; accepted February 23, 2010. 13 Activation of the c-kit receptor is mediated by its ligand stem cell factor (SCF), a cytokine that exists in soluble or membraneassociated form. 16 The membrane-bound SCF isoform, which is predominant in vivo...

Age-related regional differences in cardiac nerve growth factor expression

“…NGF plays a pivotal role in sympathetic nerve sprouting and sudden cardiac death (Chen et al 2001). An early rise of NGF can be observed rapidly after myocardial infarction (hours) and may possibly reflect an early rescue response to support myocardial healing (Meloni et al 2010). Unfortunately, NGF also causes inhomogeneity of sympathetic innervation in the infarction border zone thereby promoting lethal arrhythmias (Zhou et al 2004).…”

Reduced NGF-Serum Concentrations in Coronary Artery Disease Patients Increase after Coronary Artery Bypass Grafting

“…This is line with recent findings of NGF-expression following myocardial infarction in a mouse model. In the same study, Meloni and colleagues reported that NGF overexpression sustained its capacity to improve cardiac function and to promote angiogenesis 14 days after MI, only under experimental conditions however [13]. Another clinical study demonstrated that NGF level is significantly low in human coronary arteries with advanced atherosclerotic lesions [3] and reduced NGF levels were postulated to contribute to the pathogenesis of heart failure [29,30].…”

“…It was previously demonstrated that NGF, via TrkA, promotes angiogenesis and endothelial cells (ECs) survival through a mechanism involving the serine/threonine kinase Akt (also known as protein kinase B) [12]. Recently, it was shown that NGF elicits pleiotropic beneficial actions in the post-myocardial infarction heart [13]. There is increasing evidence that there are two different trends in NGF expression after MI: an increase in the first phase within the first few hours and an opposite profile (decrease) after presentation of heart failure [14].…”

Rita Levi-Montalcini: Presence in The Absence

“…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).…”