期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 3, 页码 1392-1404出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI99934
关键词
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资金
- Heart and Stroke Foundation of Ontario (HSFO) [T6757, NA6997, CI6824]
- Canadian Institutes of Health Research (CIHR) [PJT 162205]
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.
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