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Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α
M. Ahsan Siraj, … , Peter Backx, Mansoor Husain
M. Ahsan Siraj, … , Peter Backx, Mansoor Husain
Published January 27, 2020
Citation Information: J Clin Invest. 2020;130(3):1392-1404. https://doi.org/10.1172/JCI99934.
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Research Article Cardiology Metabolism Article has an altmetric score of 15

Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α

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Abstract

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.

Authors

M. Ahsan Siraj, Dhanwantee Mundil, Sanja Beca, Abdul Momen, Eric A. Shikatani, Talat Afroze, Xuetao Sun, Ying Liu, Siavash Ghaffari, Warren Lee, Michael B. Wheeler, Gordon Keller, Peter Backx, Mansoor Husain

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Figure 7

GLP-1(28–36) augments glucose utilization, decreases FAO, and activates sAC through MTPα.

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GLP-1(28–36) augments glucose utilization, decreases FAO, and activates ...
(A) Mouse caSMCs were transfected with a combination of 4 MTPα-specific siRNAs, and relative Mtpa mRNA expression was measured by reverse transcription PCR versus control siRNA. Data were normalized to β-microglobulin and EGFP housekeeping genes (see Supplemental Methods) and are presented as a percentage of mRNA expression of the control siRNA. n = 7 separate experiments. (B) Representative Western blot and quantitative densitometric analysis of 83-kDa MTPα protein expression in lysates from caSMCs transfected with MTPα siRNA, control siRNA, or no siRNA. Data are presented as a percentage of MTPα protein expression versus the loading control GAPDH (n = 3). (C) FAO in caSMCs was measured with a Seahorse extracellular flux analyzer as the OCR within 24 hours of transfection with MTPα siRNA (gray bars) or control siRNA (white bars) and pretreated with 100 nM GLP-1(28–36) twenty minutes before the mitochondrial stress test. Basal respiration and palmitic acid oxidation were measured in cells transfected with MTPα siRNA (gray bars) or control siRNA (white bars) (n = 7/treatment, each in triplicate). (D) Glycolysis was measured as the ECAR in caSMCs treated with MTPα siRNA (gray bars) or control siRNA (white bars) and pretreated with 100 nM GLP-1(28–36) or scrambled control (n = 3/treatment, each in triplicate). (E) Mitochondrial glucose oxidation was calculated in caSMCs treated with MTPα siRNA (black bars) or control siRNA (white bars) and pretreated with 100 nM GLP-1(28–36) or scrambled control (n = 3/treatment, each in triplicate). (F) Intracellular cAMP accumulation in MTPα-transfected caSMCs (gray bars) and control siRNA–transfected caSMCs (white bars), shown after pretreatment with GLP-1(28–36), with or without KH7, Ddox, or forskolin. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA (A, B, D, and E) or 2-way ANOVA (C and F) with Bonferroni’s post hoc test.

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