Metabolic phenotyping of murine hearts overexpressing constitutively active soluble guanylate cyclase
Bibliographic record
Abstract
Although enhanced cGMP signaling can prevent hypertrophy, mechanisms underlying this cardioprotective effect are not well understood. In this study, we assessed the potential involvement of alterations in myocardial energy substrate metabolism, a parameter known to be determinant in the development of hypertrophy. We used mice overexpressing a constitutively active soluble guanylate cyclase in a cardiomyocyte-specific manner (GC+/0) and ex vivo heart perfusion at physiological workload with 13C-labeled substrates. Compared to controls, hearts from GC+/0 mice displayed a 38±9% lower contribution of exogenous fatty acids to acetyl-CoA formation, while that of carbohydrates remained unchanged despite a two-fold increase in glycolysis. The lower contribution of exogenous fatty acids to energy production was not associated with changes in energy demand or supply (contractile function, oxygen consumption, tissue acetyl-CoA or CoA levels, citric acid cycle flux rate) or the regulation of ?-oxidation (acetyl-CoA carboxylase activity, tissue malonyl-CoA levels). However, GC+/0 hearts showed a two-fold increase in the incorporation of exogenous oleate into triglycerides. Furthermore, a concomitant increase in triglyceride hydrolysis is consistent with our findings of a greater abundance of hormone sensitive lipase (HSL) protein (46±6%) and mRNA (22±4%) as well as a 37±13% decrease in its phosphorylation level at Ser-565. The latter covalent modification inhibits HSL and is regulated by AMP-activated protein kinase (AMPK), whose phosphorylation at its activating site Thr-172 was also reduced by 37±13%. These changes in exogenous fatty acid trafficking in GC+/0 hearts appear to be functionally relevant, as demonstrated by their resistance to fasting-induced myocardial triglyceride accumulation. This raises the possibility that enhanced cGMP signaling in cardiomyocytes may protect the heart from fatty acid-induced toxic effects, either as part of its anti-hypertrophic ef
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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) | 0.001 | 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".