Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation.
Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation.
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DOI：
10.1016/j.bcp.2016.01.013
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发表时间：
2016-03-15
影响因子：
5.8
通讯作者：
Chiong M
中科院分区：
文献类型：
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作者：
Torres G;Morales PE;García-Miguel M;Norambuena-Soto I;Cartes-Saavedra B;Vidal-Peña G;Moncada-Ruff D;Sanhueza-Olivares F;San Martín A;Chiong M
胰高血糖素样肽-1(GLP-1)是一种胃肠道对食物摄取作出反应的神经内分泌激素。GLP-1通过刺激依赖葡萄糖的胰岛素分泌、抑制胰高血糖素的分泌、抑制胃排空、减少食欲和食物摄入量，在血糖稳态中起着非常重要的作用。由于这些作用，GLP-1多肽模拟物艾塞那肽成为治疗2型糖尿病最有前途的新药之一。体内应用GLP-1或埃塞那肽可防止血管内皮损伤和动脉粥样硬化病变形成所致的新生内膜层形成。GLP-1是否通过控制线粒体动力学来调控血管平滑肌细胞(VSMC)的迁移和增殖尚不清楚。在这份报告中，我们发现GLP-1以PKA依赖的方式促进VSMC细胞系A7r5的线粒体融合和活性。GLP-1诱导线粒体分裂蛋白Drp1中Ser-637的磷酸化，降低了Drp1线粒体的定位。GLP-1抑制PDGF-BB诱导的VSMC迁移和增殖，其作用可被过表达野生型Drp1抑制，可被DRp1抑制剂Mdivi-1模拟，并可通过过表达显性负向Drp1来抑制。这些结果表明，GLP-1通过PKA/Drp1信号通路刺激线粒体融合，增加线粒体活性，减少PDGF-BB诱导的VSMC去分化。我们的数据表明，GLP-1通过线粒体动力学依赖的机制抑制血管重构。
Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone produced by gastrointestinal tract in response to food ingestion. GLP-1 plays a very important role in the glucose homeostasis by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, reducing appetite and food intake. Because of these actions, the GLP-1 peptide-mimetic exenatide is one of the most promising new medicine for the treatment of type 2 diabetes. In vivo treatments with GLP-1 or exenatide prevent neo-intima layer formation in response to endothelial damage and atherosclerotic lesion formation in aortic tissue. Whether GLP-1 modulates vascular smooth muscle cell (VSMC) migration and proliferation by controlling mitochondrial dynamics is unknown. In this report, we showed that GLP-1 increased mitochondrial fusion and activity in a PKA-dependent manner in the VSMC cell line A7r5. GLP-1 induced a Ser-637 phosphorylation in the mitochondrial fission protein Drp1, and decreased Drp1 mitochondrial localization. GLP-1 inhibited PDGF-BB-induced VSMC migration and proliferation, actions inhibited by overexpressing wild type Drp1 and mimicked by the Drp1 inhibitor Mdivi-1 and by overexpressing dominant negative Drp1. These results show that GLP-1 stimulates mitochondrial fusion, increases mitochondrial activity and decreases PDGF-BB-induced VSMC dedifferentiation by a PKA/Drp1 signaling pathway. Our data suggest that GLP-1 inhibits vascular remodeling through a mitochondrial dynamics-dependent mechanism.