Beta-adrenoceptor signal transduction in high-output heart failure due to aortocaval shunt in rat
Bibliographic record
Abstract
The failing heart is characterized by blunted B-adrenoceptor (B-AR) responses associated with a number of changes in the signal transduction pathway including downregulation of B-ARs, increased expression of inhibitory G-proteins and G-protein coupled receptor kinases (GRKs) and impaired adenylyl cyclase (AC) activities. However, a careful review of the literature reveals that most types of heart failure in human and experimental models used to study B-AR signaling are associated with low cardiac output heart failure with significant fibrosis in the myocardium. No information is available regarding the regulation of B-AR signal transduction in heart failure with a high-output status without fibrosis. Therefore, the objective of this work is to use a high-output heart failure model without fibrosis and examine the status of B-AR signaling. To reach this aim, we first characterized a high-output model induced by an aortocaval shunt from several aspects including general features, morphology and histology of the heart, circulatory congestion, hemodynamics and contractile function in vivo and in vitro. The results demonstrated that the development of hypertrophy and heart failure typically occurred in three stages: developing hypertrophic stage (first two weeks after the induction of shunt), established hypertrophic stage (2-8 weeks) and decompensated hypertrophic or failing stage (8-16 weeks). The failing stage is characterized by dramatic hypertrophy of both left (LV) and right (RV) ventricles with signs of circulatory congestion, decreased in vivo and in vitro cardiac performance and shift of myosin heavy chain isoforms. However, the response of the failing heart to B-AR stimulation was not blunted but instead showed stimulation of contractile function. To investigate the mechanisms underlying the enhanced B-AR response in aortocaval shunted animals, we examined changes at the receptor level. Agonist binding experiments showed a selective increase in density of B 1-AR but not B2-AR, without any changes in the affinities. Western blot experiments confirmed that the increase in B1-AR density is due to an enhanced expression of protein levels rather than an increased externalization of receptors. However, the steady state mRNA level of B1-AR was not altered indicating an increased translational rate or decreased protein degradation underlying the increased B 1-AR protein expression.
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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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".