Identification of the prosurvival activity of nerve growth factor on cardiac myocytes

Abstract

Neurotrophins (NTs) control neuron survival and regeneration. Recent research showed that NTs possess cardiovascular actions. In this study, we investigated the hypothesis that the NT nerve growth factor (NGF) prevents cardiomyocyte apoptosis. We demonstrated that cultured rat neonatal cardiomyocytes (RNCMs) produce NGF and express its trkA (tropomyosin-related receptor A (NGF high-affinity receptor)) receptor. RNCMs given a neutralizing antibody for NGF or the trkA inhibitor K252a underwent apoptosis, thus suggesting that NGF is an endogenous prosurvival factor for cardiomyocytes. Adenovirus (Ad)-mediated NGF overexpression protected RNCMs from apoptosis induced by either hypoxia/reoxygenation or angiotensin II (AngII). Similarly, recombinant NGF inhibited AngII-induced apoptosis in isolated rat adult cardiomyocytes. Finally, in a rat model of myocardial infarction, NGF gene transfer promoted cardiomyocyte survival. In RNCMs, recombinant NGF induced trkA phosphorylation, followed by Ser473 phosphorylation and nuclear translocation of phospho-protein kinase B (Akt). In response to Akt activation, Forkhead transcription factors Foxo-3a and Foxo-1 were phosphorylated and excluded from the nucleus. The prosurvival effect of adenoviral vector carrying the human NGF gene was inhibited in vitro by K252a, LY294002 (a panphosphatidyl inositol 3-kinase -PI3K -inhibitor), an Akt small interfering RNA, and adenoviruses carrying a dominant negative mutant form of Akt (Ad.DN.Akt) or an Akt-resistant Foxo-3a (Ad. . These results newly demonstrate the cardiac prosurvival action of NGF and provide mechanistic information on the signaling pathway, which encompasses trkA, PI3K-Akt, and Foxo. Neurotrophins (NTs) were initially considered for their prosurvival and regenerative actions on the nervous system. These beneficial actions of NTs are mediated by their tropomyosin-related kinase receptors (trks), which are tyrosin kinases.1,2 Recent studies have unraveled the potential of nerve growth factor (NGF) and other NTs for vascular biology.3-7 Our group discovered that NGF protects endothelial cells and skeletal myocytes from apoptosis and promotes neovascularization in murine ischemic limb muscles and diabetic skin wounds. 3,5,6 We demonstrated the involvement of protein kinase B (Akt) in NGF-induced angiogenesis. 3Although others already tracked the presence of NGF in the heart and isolated cardiomyocytes, [8][9][10][11] the hypothesis that NGF controls cardiomyocyte survival was, to the best of our knowledge, never investigated.In noncardiovascular cells, NGF, via Akt, promotes the nuclear exclusion of Foxo-3a and Foxo-1, two members of the Forkhead box, class O (Foxo) subfamily of Forkhead transcription factors, which stimulate cell death.12 Nuclear localization of Foxo activates several Foxo-responsive genes, including the proapoptotic TNFa, Fas ligand, and Bim. [13][14][15][16] Akt-dependent Foxo phosphorylation inactivates the Foxo nuclear translocation signal and promotes the interaction of Foxo with 14-3-3 proteins, thus k...

Age-related regional differences in cardiac nerve growth factor expression

“…In general, an increase of NGF expression can be observed both in atria and ventricles. Since NGF also exerts anti-apoptotic effects via its main receptor TrkA (Caporali et al 2008), the observed NGF increase may in fact represent a reflex mechanism to an increased degree of apoptosis in aging myocardium. Since apoptosis and fibrosis in the atria and even in healthy hearts seem to develop with age (Olivetti et al 1997;Centurione et al 2002), the continuous increase of NGF may be in line with such a hypothesis.…”

“…In parallel, NGF has been identified as a pro-survival factor for cardiomyocytes by developing anti-apoptotic effects via tyrosine kinase A (TrkA) receptor downstream signaling (Caporali et al 2008). With regard to its pivotal role in the integrity of cellular and subcellular systems, the autonomic nervous system has been further shown to be involved in heart rate, rhythm, and contractility (Wasmund et al 2003;Meyer et al 2010).…”

The p75 neurotrophin receptor, semaphorins, and sympathetic traffic in the heart

“…More recently, NGF has been shown to be present in neonatal rat myocytes, where it acts as an autocrine survival factor. In addition, increasing the expression of NGF protected the cells from ANG II-induced apoptosis, and, in a rat model of myocardial infarction, NGF gene transfer promoted cardiomyocyte survival (10). Similarly, BDNF gene deletion severely affects heart development, leading to premature death in mice (14,16), and mice lacking the receptor for BDNF (TrkB) die immediately after birth (1).…”

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

“…The interaction between NGF and its receptor in cardiomyocytes causes a prosurvival signal of transcriptional factors [31]. For several cardiac diseases (MI, CAD) Rana and colleagues reported that cellular stretch leads to a decrease of NGF mRNA and protein expression in cardiomyocytes [32].…”