GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway.

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.

• Authors: Ying Ying, Huazhang Zhu, Zhen Liang, Xiaosong Ma, Shiwei Li
• Journal: Journal of molecular endocrinology (J Mol Endocrinol) Vol. 55 Issue 3 Pg. 245-62 (Dec 2015) ISSN: 1479-6813 [Electronic] England
• PMID: 26386043 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The authors.

Chemical References

• CD36 Antigens
• Cardiotonic Agents
• Glucagon-Like Peptide-1 Receptor
• Palmitates
• RNA, Small Interfering
• beta Catenin
• Glucagon-Like Peptide 1
• Glycogen Synthase Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects, genetics)
• CD36 Antigens (metabolism)
• Cardiotonic Agents (pharmacology)
• Cell Survival (genetics)
• Gene Knockdown Techniques
• Glucagon-Like Peptide 1 (pharmacology)
• Glucagon-Like Peptide-1 Receptor (metabolism)
• Glycogen Synthase Kinases (metabolism)
• Lipid Metabolism
• Myocytes, Cardiac (drug effects, metabolism)
• Palmitates (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Signal Transduction (drug effects)
• beta Catenin (genetics, metabolism)