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Exendin-4 通过蛋白激酶 A(PKA)、磷脂酰肌醇 3-激酶(PI3K)、内皮型一氧化氮合酶(eNOS)、p38 丝裂原活化蛋白激酶(p38 MAPK)和 c-Jun N-terminal kinase(JNK)通路保护血管内皮细胞免受脂肪凋亡。

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways.

机构信息

Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.

出版信息

J Mol Endocrinol. 2013 Mar 18;50(2):229-41. doi: 10.1530/JME-12-0166. Print 2013 Apr.

Abstract

Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7-36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7-36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti-apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism.

摘要

实验研究表明内皮细胞在维持血管稳态方面发挥着重要作用。我们之前曾报道,人冠状动脉内皮细胞(HCAEC)表达胰高血糖素样肽 1(GLP1)受体,而稳定的 GLP1 类似物 exendin-4 能够激活该受体,导致细胞增殖增加。在这里,我们研究了 exendin-4 和天然 GLP1(7-36)对 HCAEC 脂肪凋亡及其潜在机制的影响。用棕榈酸孵育细胞后,通过 DNA 片段化和 caspase-3 激活评估细胞凋亡。分析了一氧化氮(NO)和活性氧(ROS)。还研究了 GLP1 受体激活、PKA、PI3K/Akt、eNOS、p38 MAPK 和 JNK 依赖性途径,以及 eNOS 的基因沉默转染。棕榈酸诱导的细胞凋亡刺激细胞释放 NO 和 ROS,同时上调 eNOS,这需要激活 p38 MAPK 和 JNK。exendin-4 恢复了 NO 和 ROS 产生之间的失衡,其中 ROS 产生减少,NO 产生进一步增加。exendin-4 和 GLP1(7-36)孵育可保护 HCAEC 免受脂肪凋亡,该作用被 PKA、PI3K/Akt、eNOS、p38 MAPK 和 JNK 抑制剂阻断。eNOS 的基因沉默也消除了 exendin-4 提供的抗凋亡作用。我们的结果支持这样一种观点,即 GLP1 受体激动剂由于脂毒性而恢复 eNOS 诱导的 ROS 产生,并且此类激动剂通过 GLP1 受体依赖的机制通过 PKA-PI3K/Akt-eNOS-p38 MAPK-JNK 依赖性途径保护免受脂肪凋亡。

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