Abstract 4141421: Soluble adenylyl cyclase prevents cardiac rupture and adverse ventricular remodeling after myocardial infarction.
Bibliographic record
Abstract
Background: The ubiquitous second messenger cyclic adenosine monophosphate (cAMP) plays a key role in post-myocardial infarction [MI] remodeling, influencing apoptosis, inflammation, fibrosis and metabolism. Unlike transmembrane activators of cAMP, soluble adenylyl cyclase (sAC) represents a unique source of intracellular and mitochondrial cAMP, and metabolic sensor due to its ability to regulate oxidative metabolism and cell survival. However, a role for sAC in post-MI remodeling was not known. Methods and Results: Permanent LAD ligation was used to induce experimental MI in 10-12 wk old sAC knockout ( sAC -/- ) mice and wild-type littermates ( sAC +/+ ) [ n =26-31/group]. Compared to wild-type, sAC -/- mice had more cardiac rupture events (17/26 vs. 13/31) and reduced survival at 28-d post-MI (35 vs. 58%, P<0.05). Echocardiography showed more cardiac dysfunction in sAC -/- mice (LVEF: 20±4 vs. 28±4%, P<0.05). Heart to body weight ratio was higher in sAC -/- mice (9.1±1.5 vs. 7.7±0.3 mg/g, P<0.05 ) with no differences in lung to body weight [n=15/group]. Importantly, no structural or functional cardiac differences were found between sham-operated sAC -/- and sAC +/+ mice [n=6 each]. To elucidate underlying mechanisms, we assayed infarct size, hemodynamics, inflammation and fibrosis at 3-d post-MI, a time point that precedes cardiac rupture ( n =10 each). Sections stained with 2,3,5-triphenyltetrazolium chloride reveal larger infarcts in sAC -/- mice (43±2 vs. 37±2%, P<0.05). Pressure-volume loops show lower LVEF (31±1% vs. 34±1%, P<0.05), cardiac output (21,634±825 vs. 25,515±612 µl/min, P<0.01), and stroke volume (39±1 vs. 46±1 µl, P<0.001) in sAC -/- mice. Luminex® multiplex assay for cytokines and chemokines revealed higher serum TNFα (14±1.6 vs. 8.4±1 pg/ml), CCL5/RANTES (66.6±7.2 vs. 36.3±5 pg/ml) and MCP-1 (81.8±15 vs. 50±11.4 pg/ml) levels in sAC -/- vs. sAC +/+ mice (P<0.05 for all comparisons), with no differences in IL-6, IL-1β, INF-γ, GM-CSF, G-CSF, IL-10, IL-12 and TGF-β. Finally, Masson’s trichrome staining demonstrated no differences in interstitial or perivascular fibrosis in sAC -/- vs. sAC +/+ hearts. Conclusion: In an experimental mouse model of MI, sAC prevents cardiac rupture and adverse cardiac remodeling by reducing infarct size, improving cardiac function and limiting specific inflammatory cytokines. Further studies are needed to define which cell-types expressing sAC mediate these findings.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".