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.
View: Text | PDF
Research Article Cardiology Metabolism

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

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

×

Figure 1

Pretreatment with GLP-1(28–36) reduces infarct size in mice and provides direct GLP-1R–independent cardioprotection in isolated mouse hearts.

Options: View larger image (or click on image) Download as PowerPoint
Pretreatment with GLP-1(28–36) reduces infarct size in mice and provides...
(A) Schematic of the in vivo animal protocol. (B) Representative photomicrographs of TTC-stained heart sections show infarcted (white) versus viable (red) tissue on day 4 after MI. Smaller infarct areas were observed in hearts treated with GLP-1(28–36) or GLP-1 (positive controls) as compared with hearts treated with saline or scrambled(28–36) (Scram) (negative controls). (C) Grouped data showing quantification of infarct size as a percentage of LV surface area on day 4 after MI in WT mice pretreated for 14 days with saline (n = 9), scrambled(28–36) (both 18.5 nmol/kg/day; n = 7), GLP-1(28–36), or GLP-1 (3.5 pmol/kg/min; n = 13). (D) IRI protocol of retrograde, nonrecirculating Langendorff perfusion of isolated hearts from male 10- to 12-week-old WT or Glp1r–/– mice. (E) Representative tracings showing LVDP recordings from isolated, perfused WT hearts treated with GLP-1(28–36) or GLP-1 or with buffer only or scrambled(28–36) (Scram) controls. (F) LVDP recovery expressed as a percentage of LVDP at the end of reperfusion over LVDP before ischemia. LVDP recovery is shown in hearts perfused with 6 nM GLP-1(28–36), scrambled(28–36) control, or buffer-only control, or with 0.3 nM GLP-1 (n = 4–13 WT mice/group; gray bars; n = 3–5 Glp1r–/– mice/group; white bars). (G) LDH release into coronary effluents from perfused WT mouse hearts, measured by ELISA at timed intervals between 10 and 40 minutes of reperfusion and normalized to coronary flow (mL/min/g heart weight) (n = 3). Data represent the mean ± SEM. *P < 0.05 and ***P < 0.001 versus the corresponding control, by 1-way ANOVA with Bonferroni’s post hoc test. Cntl, control.