4805GLP-1(28–36) prevents ischemic cardiac injury by modulating metabolism and activating soluble adenylyl cyclase in coronary vascular cells
Bibliographic record
Abstract
Background: Cardiovascular disease (CVD) is increasingly attributable to type-2 diabetes (T2D) and obesity, with the incidence of T2D predicted to double by 2030. However, mechanisms underlying the pathophysiology of CVD in T2D are poorly understood. Pre-clinical studies in animals and recent human clinical trials have demonstrated robust cardioprotective actions of incretin glucagon-like peptide-1 (GLP-1), related peptides and drugs. How GLP-1 prevents acute myocardial ischemia-reperfusion injury (IRI) as well as chronic myocardial ischemic injury has not been established. We previously described that GLP-1(28–36), a small metabolite of GLP-1, is as protective as the parent peptide in ex vivo isolated heart IRI and in vivo experimental myocardial infarction (MI) models in mice, and that these effects require soluble adenylyl cyclase (sAC), but not the known GLP-1 receptor. Here we define the molecular mechanisms and cell types in which GLP-1(28–36) activates sAC. Methods and results: Immunoblots reveal that mouse and human coronary artery smooth muscle cells (caSMC) and human coronary artery endothelial cells (caEC) express sAC, while mouse neonatal ventricular cardiomyocytes (CM), a mouse atrial CM cell line (HL-1), and human embryonic stem cell (ESC)-derived CM do not. Using pharmacological inhibitors of sAC, sAC-null mice and siRNA against sAC, we demonstrate that GLP-1(28–36) causes sAC-dependent increases in cAMP, activation of PKA, and cytoprotection from oxidative stress injury in both mouse and human caSMC. Moreover, GLP-1(28–36) increases cAMP responses in human caEC and probenecid, which blocks the anion (HCO3) entry required for sAC activity, abrogates these effects. By contrast, human ESC-derived CM shows no cAMP or cytoprotection responses to GLP-1(28–36). Next, we show in caSMC that GLP-1(28–36) causes dose-dependent increases in intracellular ATP, a known substrate of sAC. Affinity pull-down experiments using biotinylated-GLP-1(28–36), proteomic analysis with mass spectrometry, and confirmatory immunoblots suggest that GLP-1(28–36) interacts with mitochondrial trifunctional protein alpha (MTPα), an enzyme involved in fatty acid metabolism, and does not directly interact with sAC. Using extracellular flux analysis of caSMC and caEC, and siRNA against MTPα, we demonstrate that the ability of GLP-1(28–36) to shift substrate utilization towards the energy efficient glucose utilization and away from the high energy consuming fatty acid oxidation is dependent on MTPα.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".