Abstract
Activation of apoptosis in cardiomyocytes by saturated palmitic acids contributes to cardiac dysfunction in diabetic cardiomyopathy. Beta-catenin (b-catenin) is a transcriptional regulator of several genes involved in survival/anti-apoptosis. However, its role in palmitate-induced cardiomyocyte apoptosis remains unclear. Glucagon-like peptide 1 (GLP1) has been shown to exhibit potential cardioprotective properties. This study was designed to evaluate the role of b-catenin signalling in palmitate-induced cardiomyocyte apoptosis and the molecular mechanism underlying the protective effects of GLP1 on palmitate-stressed cardiomyocytes. Exposure of neonatal rat cardiomyocytes to palmitate increased the fatty acid transporter CD36-mediated intracellular lipid accumulation and cardiomyocyte apoptosis, decreased accumulation and nuclear translocation of active b-catenin, and reduced expression of b-catenin target protein survivin and BCL2. These detrimental effects of palmitate were significantly attenuated by GLP1 co-treatment. However, the anti-apoptotic effects of GLP1 were markedly abolished when b-catenin was silenced with a specific short hairpin RNA. Furthermore, analysis of the upstream molecules and mechanisms responsible for GLP1-associated cardiac protection revealed that GLP1 restored the decreased phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3b (GSK3b) in palmitate-stimulated cardiomyocytes. In contrast, inhibition of Akt with an Akt-specific inhibitor MK2206 or blockade of GLP1 receptor (GLP1R) with a competitive antagonist exendin-(9–39) significantly abrogated the GLP1-mediated activation of GSK3b/b-catenin signalling, leading to increased apoptosis in palmitate-stressed cardiomyocytes. Collectively, our results demonstrated for the first time that the attenuated b-catenin signalling may contribute to palmitate-induced cardiomyocyte apoptosis, while GLP1 can protect cardiomyocytes from palmitate-induced apoptosis through activation of GLP1R/Akt/GSK3b-mediated b-catenin signalling.
Highlights
High levels of plasma free fatty acid seen in type 2 diabetes and obesity (Fraze et al 1985) have been proposed as a potential mechanism for the development of diabetic/ lipotoxic cardiomyopathy (Rodrigues et al 1995, Zhou et al 2000, Boudina & Abel 2007)
This study represents the first demonstration that b-catenin signalling was attenuated in a model of palmitate-induced cardiomyocyte apoptosis, which was restored by Glucagon-like peptide 1 (GLP1) treatment
Our results from the present study showed that palmitate induced decreased accumulation of b-catenin in the cytosol and nucleus of isolated cardiomyocytes, which was accompanied by the downregulated expression of survivin and BCL2, the important downstream target genes of b-catenin (Behrens et al 1996, Miller et al 1999)
Summary
High levels of plasma free fatty acid seen in type 2 diabetes and obesity (Fraze et al 1985) have been proposed as a potential mechanism for the development of diabetic/ lipotoxic cardiomyopathy (Rodrigues et al 1995, Zhou et al 2000, Boudina & Abel 2007). Wnt and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling pathways converge through beta-catenin (b-catenin)-mediated regulation of cell survival/apoptosis in different cell types including cardiomyocytes (Ding et al 2000, Fukumoto et al 2001, Almeida et al 2005). In response to Wnt or PI3K/Akt signals, inactivation of GSK3B through phosphorylation of serine 9 residue (Ser9) (Ding et al 2000) leads to the stabilization, cytosolic accumulation and subsequent translocation of b-catenin to the nucleus to transactivate the expression of specific genes involved in cell survival and proliferation (Behrens et al 1996, Miller et al 1999). Recent studies have suggested that the PI3K/GSK3B/b-catenin signalling pathway shows potential anti-apoptotic effects after myocardial infarction (MI) in rat ischemic preconditioning (Kaga et al 2006) or post-conditioning (Wu et al 2012) models. The role of b-catenin signalling in the context of palmitate-induced cardiomyocyte apoptosis has not been determined far
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