GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway.
GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway.
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GLP1 通过 Akt/GSK3b/b-catenin 通路保护心肌细胞免受棕榈酸酯诱导的细胞凋亡
DOI：
10.1530/jme-15-0155
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发表时间：
2015-12
影响因子：
3.5
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Ying Y;Zhu H;Liang Z;Ma X;Li S
饱和棕榈酸激活心肌细胞凋亡与糖尿病心肌病心功能不全的关系。β-连环蛋白（β-catenin）是参与生存/抗凋亡的几个基因的转录调节因子。然而，其在棕榈酸诱导的心肌细胞凋亡中的作用仍不清楚。胰高血糖素样肽1（GLP 1）已被证明具有潜在的心脏保护特性。本研究旨在评估β-连环蛋白信号转导在棕榈酸诱导的心肌细胞凋亡中的作用以及GLP 1对棕榈酸应激心肌细胞保护作用的分子机制。暴露于棕榈酸的新生大鼠心肌细胞增加了脂肪酸转运蛋白CD 36介导的细胞内脂质积聚和心肌细胞凋亡，减少了活性β-连环蛋白的积聚和核转位，并减少了β-连环蛋白靶蛋白生存素和BCL 2的表达。棕榈酸酯的这些有害作用通过GLP 1共处理显著减弱。然而，当用特异性短发夹RNA沉默b-连环蛋白时，GLP 1的抗凋亡作用显著消除。此外，对负责GLP 1相关心脏保护的上游分子和机制的分析表明，GLP 1恢复了棕榈酸刺激的心肌细胞中蛋白激酶B（Akt）和糖原合成酶激酶-3 B（GSK 3 B）的磷酸化降低。相比之下，Akt特异性抑制剂MK 2206抑制Akt或竞争性拮抗剂exendin-（9-39）阻断GLP 1受体（GLP 1 R）显著消除了GLP 1介导的GSK 3b/b-连环蛋白信号转导激活，导致棕榈酸应激心肌细胞凋亡增加。总的来说，我们的研究结果首次表明，减弱的β-连环蛋白信号可能有助于棕榈酸诱导的心肌细胞凋亡，而GLP 1可以通过激活GLP 1 R/Akt/GSK 3b介导的β-连环蛋白信号来保护心肌细胞免受棕榈酸诱导的凋亡。
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.