Cardiomyocyte-targeted Gi signaling promotes cardiac repair under sustained adrenergic stress in mice
Bibliographic record
Abstract
Enhanced cholinergic signaling is associated with cardioprotection, with cardiomyocyte Gi activation via M2 muscarinic receptors proposed as a contributing mechanism. To test this therapeutic strategy, we engineered Myh6-Cre/hM4Di mice to selectively activate Gi signaling in cardiomyocytes (CM-Gi + ) using DREADD technology. Gi pathway engagement was temporally controlled through clozapine-N-oxide (CNO) administration, and we evaluated its impact in a model of adrenergic-induced cardiomyopathy. In vitro, CNO reduced myocyte shortening in Myh6-Cre/hM4Di cardiomyocytes. It also suppressed isoproterenol (ISO)-induced contractility enhancement and phosphorylation of PKA target motifs, consistent with Gi activation. In vivo, a 7-day ISO regimen induced cardiac hypertrophy, inflammation, and expression of fibrosis markers, all prevented by CNO-driven CM-Gi + signaling. This intervention also preserved cardiomyocyte viability under ISO challenge in vitro and in vivo, underscoring its cytoprotective effects. To evaluate the therapeutic potential of this cell-targeted approach at a more advanced stage of injury, CNO treatment was initiated on day 4 of a 7-day ISO protocol, when cell death and inflammation are prominent. Echocardiographic, histological and flow cytometry analyses demonstrated that delayed CM-Gi + stimulation restored cardiac function and prevented macrophage accumulation. Contractility assessments confirmed normalization of myocyte function in ISO-treated mice, supporting the concept of cardiomyocyte recovery. Mechanistically, these beneficial effects were associated with reduced cardiac infiltration of CCR2 + monocytes, key drivers of adverse remodeling. Our findings identify cardiomyocyte-specific Gi activation as a cytoprotective strategy that promotes myocardial repair under sustained adrenergic stress. This work lays the foundation for precision cell-targeted therapies aimed at modulating cholinergic/Gi signaling in the injured heart.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".