Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α
Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α
复制标题
DOI：
10.1172/jci99934
复制
发表时间：
2020-03-02
影响因子：
15.9
通讯作者：
Husain, Mansoor
中科院分区：
文献类型：
--
作者：
Siraj, M. Ahsan;Mundil, Dhanwantee;Husain, Mansoor
胰高血糖素样肽1（GLP-1）介导心脏保护作用的机制尚不清楚。在这里，我们在离体和体内缺血性损伤模型中表明，用GLP-1（28-36）（GLP-1的中性内肽酶产生的（NEP产生的）代谢物）治疗与GLP-1一样具有心脏保护作用，并且通过扰乱其氨基酸序列而被消除。GLP-1（28-36）通过巨胞饮作用进入人冠状动脉内皮细胞（caEC），并直接作用于小鼠和人冠状动脉平滑肌细胞（caSMC）和caEC，导致cAMP的可溶性腺苷酸环化酶Adcy 70依赖性（sAC依赖性）增加、蛋白激酶A活化和细胞保护免受氧化损伤。GLP-1（28-36）通过增加细胞内ATP水平调节sAC，伴随sAC（-/-）细胞中cAMP蓄积的损失。我们鉴定了线粒体三功能蛋白-α（MTP α）作为GLP-1（28-36）的结合伴侣，并证明GLP-1（28-36）将底物利用从耗氧脂肪酸代谢转移到节省氧气的糖酵解和葡萄糖氧化以及增加cAMP水平的能力依赖于MTP α。沙库巴曲对NEP的抑制作用减弱了GLP-1增加体外培养的冠状动脉血管细胞cAMP水平的能力。GLP-1（28-36）是一种小肽，靶向心肌缺血性损伤中的新分子（MTPu α和sAC）和细胞（caSMC和caEC）机制。
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 Adcy70-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-alpha (MTP alpha) 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 MTP alpha. NEP inhibition with sacubitril blunted the ability of GLP-1to increase cAMP levels in coronary vascular cells in vitro. GLP-1(28-36) is a small peptide that targets novel molecular (MTPu alpha and sAC) and cellular (caSMC and caEC) mechanisms in myocardial ischemic injury.