Glucagon-Like Peptide (GLP)-1(9-36)Amide-Mediated Cytoprotection Is Blocked by Exendin(9-39) Yet Does Not Require the Known GLP-1 Receptor
Glucagon-Like Peptide (GLP)-1(9-36)Amide-Mediated Cytoprotection Is Blocked by Exendin(9-39) Yet Does Not Require the Known GLP-1 Receptor
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DOI：
10.1210/en.2009-1197
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发表时间：
2010-04-01
期刊：
影响因子：
4.8
通讯作者：
Husain, Mansoor
中科院分区：
文献类型：
--
作者：
Ban, Kiwon;Kim, Kyoung-Han;Husain, Mansoor
广泛表达的二肽基肽酶-4酶在N末端快速裂解肠道激素胰高血糖素样肽-1 [GLP-1（7-36）酰胺]，生成GLP-1（9-36）酰胺。完整GLP-1（7-36）酰胺和GLP-1（9-36）酰胺均在啮齿动物心脏中发挥心脏保护作用;然而，对GLP-1（9-36）酰胺作用的潜在机制仍知之甚少。我们使用冠状动脉流出物的质谱来证明离体小鼠心脏将输注的GLP-1（7-36）酰胺快速转化为GLP-1（9-36）酰胺。在离体小鼠心脏的缺血-再灌注（I/R）损伤后，给予GLP-1（9-36）酰胺或毒蜥外泌肽-4改善了功能恢复并减小了梗死面积。在培养的新生小鼠心肌细胞中研究了这些肽的直接作用。GLP-1（9-36）酰胺和exendin-4均增加cAMP水平和ERK 1/2和磷酸肌醇3-激酶靶蛋白激酶B/Akt的磷酸化。在体外I/R损伤模型中，两种肽均改善小鼠心肌细胞活力，降低乳酸脱氢酶释放和caspase-3活化。ERK 1/2和磷酸肌醇3-激酶抑制剂可减弱这些作用。出乎意料的是，GLP-1（9-36）酰胺的心脏保护作用被exendin（9-39）阻断，但在Glp 1 r（-/-）心肌细胞中保留。此外，GLP-1（9-36）酰胺，而不是毒蜥外泌肽-4，改善了经历I/R损伤的人主动脉内皮细胞的存活，对一氧化氮合酶抑制剂N（G）-硝基-L-精氨酸甲酯（L-NAME）敏感。总之，我们的研究结果证明了GLP-1（9-36）酰胺与GLP-1 R激动剂毒蜥外泌肽-4的单独作用，并揭示了与经典GLP-1受体相关的GLP-1（9-36）酰胺应答性、毒蜥外泌肽（9-39）敏感性、心脏保护性信号通路的存在。（内分泌学151：1520-1531，2010）
The widely expressed dipeptidyl peptidase-4 enzyme rapidly cleaves the gut hormone glucagon-like peptide-1 [GLP-1(7-36)amide] at the N terminus to generate GLP-1(9-36)amide. Both intact GLP-1(7-36)amide and GLP-1(9-36)amide exert cardioprotective actions in rodent hearts; however, the mechanisms underlying the actions of GLP-1(9-36)amide remain poorly understood. We used mass spectrometry of coronary effluents to demonstrate that isolated mouse hearts rapidly convert infused GLP-1(7-36)amide to GLP-1(9-36)amide. After ischemia-reperfusion (I/R) injury of isolated mouse hearts, administration of GLP-1(9-36)amide or exendin-4 improved functional recovery and reduced infarct size. The direct actions of these peptides were studied in cultured neonatal mouse cardiomyocytes. Both GLP-1(9-36)amide and exendin-4 increased levels of cAMP and phosphorylation of ERK1/2 and the phosphoinositide 3-kinase target protein kinase B/Akt. In I/R injury models in vitro, both peptides improved mouse cardiomyocyte viability and reduced lactate dehydrogenase release and caspase-3 activation. These effects were attenuated by inhibitors of ERK1/2 and phosphoinositide 3-kinase. Unexpectedly, the cardioprotective actions of GLP-1(9-36) amide were blocked by exendin(9-39) yet preserved in Glp1r(-/-) cardiomyocytes. Furthermore, GLP-1(9-36)amide, but not exendin-4, improved the survival of human aortic endothelial cells undergoing I/R injury, actions sensitive to the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). In summary, our findings demonstrate separate actions for GLP-1(9-36) amide vs. the GLP-1R agonist exendin-4 and reveal the existence of a GLP-1(9-36)amide-responsive, exendin(9-39)-sensitive, cardioprotective signaling pathway distinct from that associated with the classical GLP-1 receptor. (Endocrinology 151: 1520-1531, 2010)