Mechanisms Underlying Cardioprotective Effects of Glucagon like Peptide-1 in Ischemia-reperfusion Injury
Bibliographic record
Abstract
Cardioprotective effects of glucagon-like peptide-1 (GLP-1), the GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4), and GLP-1(9-36), a cleavage product of GLP-1, were examined in ischemia-reperfusion (I/R) models of both isolated mouse hearts and cultured cardiac myocytes (CMs) using both wild-type (WT) and GLP-1R knockout (Glp1r-/-) mice. In WT hearts, GLP-1 and Ex-4 significantly improved left ventricular functional recovery vs. untreated controls following I/R, whether the drugs were administered prior to ischemia (pre-ischemia) or during reperfusion (post-ischemia). Surprisingly, the cardioprotective effects of pre- and post-ischemia treatments with GLP-1, but not Ex-4, remained evident in Glp1r-/- hearts. Although pre-ischemia infusion of GLP-1(9-36) induced lower functional recovery than untreated controls, post-ishemia infusion of GLP-1(9-36) augmented functional recovery and reduced infarct size to a similar extent to that of GLP-1 and Ex-4 in hearts from both WT and Glp1r-/- mice. Mass spectrometry was used to assay conversion of GLP-1 to GLP-1(9-36) in coronary effluents of isolated mouse hearts. Within 15 min of infusing GLP-1, significant amounts of GLP-1(9-36) were generated by the heart. By 30 min, only trace amounts of intact GLP-1 remained in coronary effluents indicating the heart rapidly converts GLP-1 to GLP-1(9-36). In CMs undergoing simulated I/R injury in vitro, both GLP-1(9-36) and Ex-4 significantly improved cell viability, LDH release and caspase-3 activation. These effects were significantly attenuated by co-treatments with LY294002, PD98059 and Ex(9-39), inhibitors of PI3K, ERK1/2, and GLP-1R respectively. The actions of Ex-4, but not GLP-1(9-36), were lost in CMs isolated from Glp1r-/- mice and only GLP-1(9-36), but not Ex-4, improved the survival of human aortic endothelial cells (HAEC) undergoing simulated I/R injury. Of note, both GLP-1 and GLP-1(9-36) treatments also demonstrated potent vasodilatory effects, as manifested by increased coronary flow rates in isolated hearts and increased diameters of pre-constricted mesenteric arteries isolated from both WT and Glp1r-/- mice. The cardioprotective effects on isolated hearts and vasodilatory effects on isolated mesenteric arteries, induced by GLP-1 was blunted by co-treatment with a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor known to block conversion of GLP-1 to GLP-1(9-36). Together, these data suggest that the beneficial effects of GLP-1 in I/R injury are mediated in part by GLP(9-36) and support the existence of a GLP-1(9-36) responsive, but Ex(9-39)-sensitive cardioprotective signaling pathway distinct from that associated with the classical GLP-1R.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".