Mechanisms mediating the cardioprotective actions of glucagon-like peptide 1 (GLP-1) were unknown. Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1(28-36), a neutral endopeptidase-generated (NEP-generated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino acid sequence. GLP-1(28-36) enters human coronary artery endothelial cells (caECs) through macropinocytosis and acts directly on mouse and human coronary artery smooth muscle cells (caSMCs) and caECs, resulting in soluble adenylyl cyclase Adcy10-dependent (sAC-dependent) increases in cAMP, activation of protein kinase A, and cytoprotection from oxidative injury. GLP-1(28-36) modulates sAC by increasing intracellular ATP levels, with accompanying cAMP accumulation lost in sAC-/- cells. We identify mitochondrial trifunctional protein-α (MTPα) as a binding partner of GLP-1(28-36) and demonstrate that the ability of GLP-1(28-36) to shift substrate utilization from oxygen-consuming fatty acid metabolism toward oxygen-sparing glycolysis and glucose oxidation and to increase cAMP levels is dependent on MTPα. NEP inhibition with sacubitril blunted the ability of GLP-1 to increase cAMP levels in coronary vascular cells in vitro. GLP-1(28-36) is a small peptide that targets novel molecular (MTPα and sAC) and cellular (caSMC and caEC) mechanisms in myocardial ischemic injury.

中文翻译：

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具有心脏保护作用的GLP-1代谢产物通过抑制线粒体三功能蛋白α来预防缺血性心脏损伤。

调解胰高血糖素样肽1（GLP-1）的心脏保护作用的机制尚不清楚。在这里，我们在体外和体内缺血性损伤模型中均显示，GLP-1（28-36）（一种中性内肽酶生成（NEP生成）的GLP-1代谢产物）的治疗与GLP-1一样具有心脏保护作用并且通过加扰其氨基酸序列而被取消。GLP-1（28-36）通过巨胞饮作用进入人冠状动脉内皮细胞（caECs），并直接作用于小鼠和人冠状动脉平滑肌细胞（caSMCs）和caECs，从而产生可溶性腺苷酸环化酶Adcy10依赖性（sAC依赖性）增加cAMP，激活蛋白激酶A和保护细胞免受氧化损伤。GLP-1（28-36）通过增加细胞内ATP水平来调节sAC，伴随的cAMP积累在sAC-/-细胞中丢失。我们确定线粒体三功能蛋白-α（MTPα）为GLP-1（28-36）的结合伴侣，并证明GLP-1（28-36）的能力将底物利用从耗氧的脂肪酸代谢转变为氧保留糖酵解和葡萄糖氧化以及增加cAMP水平取决于MTPα。沙必比尔对NEP的抑制减弱了GLP-1在体外增加冠状血管细胞中cAMP水平的能力。GLP-1（28-36）是一种小肽，在心肌缺血性损伤中靶向新型分子（MTPα和sAC）和细胞（caSMC和caEC）机制。