title: 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.affiliation: School of MedicineShenzhen University Diabetes Center, Shenzhen University, Shenzhen 518060, ChinaDepartment of GeriatricShenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China yingying@szu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ying
authors.affiliation: School of MedicineShenzhen University Diabetes Center, Shenzhen University, Shenzhen 518060, ChinaDepartment of GeriatricShenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Huazhang
authors.initials: H
authors.lastname: Zhu
authors.affiliation: School of MedicineShenzhen University Diabetes Center, Shenzhen University, Shenzhen 518060, ChinaDepartment of GeriatricShenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China School of MedicineShenzhen University Diabetes Center, Shenzhen University, Shenzhen 518060, ChinaDepartment of GeriatricShenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liang
authors.affiliation: School of MedicineShenzhen University Diabetes Center, Shenzhen University, Shenzhen 518060, ChinaDepartment of GeriatricShenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Ma
authors.affiliation: School of MedicineShenzhen University Diabetes Center, Shenzhen University, Shenzhen 518060, ChinaDepartment of GeriatricShenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D018955:CD36 Antigens / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000235:genetics; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D038341:Glycogen Synthase Kinases / Q000378:metabolism*; D050356:Lipid Metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D002316:Cardiotonic Agents; D000067757:Glucagon-Like Peptide-1 Receptor; D010168:Palmitates; D034741:RNA, Small Interfering; D051176:beta Catenin; D052216:Glucagon-Like Peptide 1; D038341:Glycogen Synthase Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; GLP1; GLP1R; GSK3B; apoptosis; b-catenin; cardiomyocytes; palmitate