Glucagon-like peptide-1 attenuates endoplasmic reticulum stress-induced apoptosis in H9c2 cardiomyocytes during hypoxia/reoxygenation through the GLP-1R/PI3K/Akt pathways
Glucagon-like peptide-1 attenuates endoplasmic reticulum stress-induced apoptosis in H9c2 cardiomyocytes during hypoxia/reoxygenation through the GLP-1R/PI3K/Akt pathways
复制标题
胰高血糖素样肽-1 通过 GLP-1R/PI3K/Akt 途径减轻缺氧/复氧期间 H9c2 心肌细胞内质网应激诱导的细胞凋亡
DOI：
10.1007/s00210-019-01625-2
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发表时间：
2019-06-01
影响因子：
3.6
通讯作者：
Gu, Xiang
中科院分区：
文献类型：
--
作者：
Guan, Gaopeng;Zhang, Jun;Gu, Xiang
内质网应激诱导的细胞凋亡是心肌缺血/再灌注损伤的主要原因。新的证据表明胰高血糖素样肽-1（GLP-1）具有潜在的心脏保护作用。然而，GLP-1参与I/R损伤的确切机制在很大程度上仍然未知。在本研究中，我们的目的是确定GLP-1是否减轻心肌细胞缺氧/复氧（H/R）损伤，并进一步阐明潜在的信号通路。结果表明，GLP-1逆转了由H/R引起的细胞凋亡率增加、乳酸脱氢酶（LDH）水平升高、细胞活力降低、Caspase-3活性升高和Bax/Bcl-2比值升高。重要的是，GLP-1显著降低了H/R诱导的ER应激蛋白（GRP 78，CHOP）和Caspase-12的表达。此外，我们发现GLP-1增加了H/R损伤的H9 c2细胞中p-Akt的表达，GLP-1对H/R诱导的损伤的保护作用被GLP-1受体（GLP-1 R）抑制剂Exendin 9 -39和PI 3 K抑制剂LY 294002阻断。Exendin 9 -39和LY 294002也阻断了GLP-1对H/R损伤后ER应激蛋白表达的下调。因此，我们已经证明GLP-1通过减轻由H/R损伤引起的ER应激诱导的细胞凋亡来发挥其心脏保护作用，并且这些作用最可能与GLP-1 R/PI 3 K/Akt信号通路的激活相关。
Endoplasmic reticulum (ER) stress-induced apoptosis is a major cause of myocardial ischemia/reperfusion (I/R) injury. Emerging evidence indicates that glucagon-like peptide-1 (GLP-1) has potential cardioprotective effects. However, the precise mechanisms underlying the involvement of GLP-1 in I/R injury remain largely unknown. In the present study, we aimed to determine whether GLP-1 attenuates hypoxia/reoxygenation (H/R) injury in cardiomyocytes and to further elucidate the underlying signaling pathway. The results indicate that GLP-1 reversed the increased apoptotic ratio, the increased lactate dehydrogenase (LDH) levels, the reduced cell viability, the increased Caspase-3 activity, and the increased Bax/Bcl-2 ratio caused by H/R. Importantly, GLP-1 significantly decreased the expression of H/R-induced ER stress proteins (GRP78, CHOP) and Caspase-12. In addition, we found that GLP-1 increased the expression of p-Akt in H9c2 cells with H/R injuries, and that the protective action of GLP-1 against H/R-induced injury was blocked by the GLP-1 receptor (GLP-1R) inhibitor Exendin9-39 and the PI3K inhibitor LY294002. Exendin9-39 and LY294002 also blocked the downregulation of ER stress protein expression by GLP-1, after H/R injury. Therefore, we have shown that GLP-1 exerts its cardioprotective effects by alleviating ER stress-induced apoptosis due to H/R injury and that these effects are most likely associated with the activation of GLP-1R/PI3K/Akt signaling pathway.