Abstract 80: PI3Kα Regulates Biomechanical Stress-induced Cytoskeletal Remodeling: A Critical Role of Gelsolin
Bibliographic record
Abstract
Background: Biomechanical stress and cytoskeletal remodeling are key determinants in pressure overload-induced heart failure. Class Ia phosphoinositide 3-kinases (PI3Ks) mediate a variety of cellular activities, in response to agonist binding to cell-surface receptors, by generating the phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) phosphoinositide lipid. Gelsolin is a Ca 2+ - and phosphoinositide-regulated actin filament severing and capping protein that is upregulated in failing human hearts and animal models of heart failure. Hypothesis: We hypothesize that PI3Kα regulates cytoskeletal remodeling through PIP 3 -mediated regulation of gelsolin. In addition, loss of gelsolin could attenuate the adverse cytoskeletal remodeling and result in increased resistance to the development of heart failure in response to pressure-overload. Methods and Results: Loss of p110α kinase activity, in two different transgenic models (PI3Kα dominant-negative (PI3KαDN) and cardiomyocyte-specific PI3Kα-null), resulted in dilated cardiomyopathy and markedly worsened cardiac dysfunction in response to transverse aortic constriction-induced pressure overload. Increased levels of mechanosensor proteins along with decreased F/G-actin ratio exhibited an uncoupling between cardiac mechanotransduction and cytoskeletal remodeling in p110α-null mice. Gelsolin activity was markedly increased in the p110α-null hearts in response to pressure-overload, whereas loss of gelsolin in PI3KαDN/gelsolin-null double mutant mice prevented the adverse cytoskeletal remodeling and preserved the cardiac function. In a murine model of chronic heart failure, loss of gelsolin prevented the pressure overload-induced cardiac dysfunction, fibrosis, and impaired cardiomyocyte contractility resulting in increased survival. Loss of gelsolin also mitigated the biomechanical stress-induced adverse cytoskeletal remodeling, via the attenuation of actin severing activity. Conclusions: We have identified a novel role of gelsolin as a mediator of adverse cytoskeletal remodeling leading to heart failure, where PI3Kα is a key regulator of gelsolin activity.
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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) | 0.001 | 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) | 0.004 | 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".