Abstract
Gab1 (Grb2 associated binding protein 1) is a member of the scaffolding/docking proteins (Gab1, Gab2, and Gab3). It is required for fibroblast cell survival and maintaining cardiac function. Very little is known about human Gab1 expression in response to chronic hypoxia. The present study examined the hypothesis that hypoxia regulates Gab1 expression in human paediatric myocardium and cultured rat cardiomyocytes. Here we showed that Gab1 is expressed in myocardial tissue in acyanotic and cyanotic children with congenital heart defects. Gab1 protein was upregulated in cyanotic compared to acyanotic hearts suggesting that Gab1 upregulation is a component of the survival program initiated by hypoxia in cyanotic children. The expression of other Gab1 interacting partners was not affected by hypoxia and Gab1 regulation. Additionally, using an in vitro model, we demonstrated that overexpressing Gab1 in neonatal cardiomyocytes, under hypoxic condition, resulted in the reduction of apoptosis suggesting a role for this protein in cardiomyocyte survival. Altogether, our data provide strong evidence that Gab1 is important for heart cell survival following hypoxic stress.
Highlights
Heart malformation during embryonic development can cause congenital heart diseases (CHD)
We investigated the effects of cyanosis on Grb2 associated binding protein 1 (Gab1) in myocardium samples from paediatric patients suffering from tetralogy of Fallot (TOF) and we examined the effects of hypoxia in primary cultures of rat neonatal cardiomyocytes on Gab1 and its possible role in cell survival
Our study revealed a significant upregulation of Gab1 protein expression in cyanotic TOF patients
Summary
Heart malformation during embryonic development can cause congenital heart diseases (CHD). We have shown that chronic hypoxia in pediatric patients with TOF triggered the expression of network of genes associated with apoptosis and reduced the expression of genes involved in myocyte contractility and function [6] This state of hypoxia in TOF children may be responsible for the susceptibility of cyanotic children to reoxygenation injury during and after surgery. Gab has been shown to exert an antiapoptotic role in mouse embryonic fibroblasts and is activated through tyrosine phosphorylation following oxidative treatment (H2O2) [12] In their investigation, Holgado-Madruga and Wong identified Gab as an important component in oxidative stress signalling with an essential role in the activation of c-Jun NH(2)-terminal kinase (JNK) and the influencing of cell survival [12]. We investigated the effects of cyanosis on Gab in myocardium samples from paediatric patients suffering from TOF and we examined the effects of hypoxia in primary cultures of rat neonatal cardiomyocytes on Gab and its possible role in cell survival
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