Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury
Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury
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DOI：
10.2337/diabetes.54.1.146
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发表时间：
2005-01-01
期刊：
影响因子：
7.7
通讯作者：
Yellon, DM
中科院分区：
文献类型：
--
作者：
Bose, AK;Mocanu, MM;Yellon, DM
胰高血糖素样肽1（GLP-1）是一种刺激胰岛素分泌的肠促胰岛素激素，也可激活胰腺和胰岛素瘤细胞中的抗凋亡信号通路，如磷酸肌醇3-激酶和促分裂原活化蛋白激酶。由于这些激酶已被证明可以保护心肌免受损伤，我们假设GLP-1可以通过这些促生存信号通路直接保护心脏免受这种损伤。采用离体灌流大鼠心脏和整体动物缺血/再灌注模型，以梗死面积作为损伤终点。在这两项研究中，与缬氨酸吡咯烷（其分解的抑制剂）或盐水组相比，在缺血前加入GLP-1显示出梗死显著减少。GLP-1受体拮抗剂exendin（9-39）、cAMP抑制剂Rp-cAMP、PI 3激酶抑制剂LY 294002和p42/44丝裂原活化蛋白激酶抑制剂UO 126在体外心脏中消除了这种保护作用。蛋白质印迹分析表明GLP-1处理组中促凋亡肽BAD的磷酸化。我们首次证明GLP-1在离体和完整的大鼠心脏中保护心肌梗死。这种保护似乎涉及激活多种促生存激酶。这一发现可能代表了这类药物的新的治疗潜力，目前正在进行临床试验，用于治疗2型糖尿病。
Glucagon-like peptide 1 (GLP-1), a gut incretin hormone that stimulates insulin secretion, also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinase in pancreatic and insulinoma cells. Since these kinases have been shown to protect against myocardial injury, we hypothesized that GLP-1 could directly protect the heart against such injury via these prosurvival signaling pathways. Both isolated perfused rat heart and whole animal models of ischemia/reperfusion were used, with infarct size measured as the end point of injury. In both studies, GLP-1 added before ischemia demonstrated a significant reduction in infarction compared with the valine pyrrolidide (an inhibitor of its breakdown) or saline groups. This protection was abolished in the in vitro hearts by the GLP-1 receptor antagonist exendin (9-39), the cAMP inhibitor Rp-cAMP, the PI3kinase inhibitor LY294002, and the p42/44 mitogen-activated protein kinase inhibitor UO126. Western blot analysis demonstrated the phosphorylation of the proapoptotic peptide BAD in the GLP-1-treated groups. We show for the first time that GLP-1 protects against myocardial infarction in the isolated and intact rat heart. This protection appears to involve activating multiple prosurvival kinases. This finding may represent a new therapeutic potential for this class of drug currently undergoing clinical trials in the treatment of type 2 diabetes.