Abstract 19538: Integrin-Linked Kinase Regulates Cardiomyocyte Calcium Signaling through Protein-Protein Interaction with Sarcoplasmic Reticulum Calcium ATPase
Bibliographic record
Abstract
The transduction of mechanical load into dynamic changes in cardiac contractility is an incompletely understood process. ILK is a Ser/Thr kinase sarcomeric Z-disk protein with known mechanoreceptor function and cardioprotective properties. We hypothesized that ILK modulates calcium signaling in the cardiomyocyte to orchestrate both mechanoreceptor function and cytoprotection. ILK immunoprecipitates (IP) from transgenic mice with cardiac overexpression of ILK showed dose-dependent co-IP of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) confirmed by mass spectroscopy. Transduction of wild type ILK upregulated SERCA2a expression, and increased the phosphorylation (Thr17) of phospholamban, in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). ILK knockdown by siRNA decreased SERCA2a expression. The upregulation of SERCA2a was not prevented by the ILK kinase small molecule inhibitor QLT0267 suggesting a scaffolding rather than catalytic effect of ILK. The beat rate response to the SERCA2a inhibitor thapsigargin (TG) in iPSC-CMs was determined by long-term measurements of electrical impedance using the xCELLigence RTCA Cardio System (Roche). ILK transduction resulted in a faster baseline beat rate compared to untreated and vector control cells (p < 0.01). TG significantly decreased beat rate with incomplete recovery after 30 hours (p < 0.01). TG also reduced beat rate in ILK-transduced cells; however, the recovery to pre-TG baseline was accelerated by the ILK transfection (time to recover 10 hr; p=0.017), consistent with increased ILK-mediated SERCA2a activity. Cardiomyocyte calcium transients were measured in human iPSC-CMs using confocal microscopy and analyzed using Origin 8.6. ILK-transduced iPSC-CMs showed a significantly reduced time constant Tau (p<0.01) and increased beat rate (p=0.01) compared to GFP-reporter control, consistent with SERCA2a-dependent increased rate of SR-mediated calcium uptake. We conclude that ILK regulates the expression and activity of SERCA2a in the cardiomyocyte. The demonstrated ILK-SERCA2a interaction provides an elegant mechanism for transduction of mechano- and stress- reception into dynamic, calcium-mediated changes in cardiomyocyte contractility.
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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".