Actin Cytoskeletal Remodeling Mediates SUN1/ARPC5 Protein Accumulation to Drive Nuclear Architectural Alteration; A Novel Signaling Axis in Pulmonary Hypertension
Bibliographic record
Abstract
Abstract Rationale Pulmonary hypertension (PH) is a deadly disease characterized by hyperproliferation and reduced apoptotic ability of pulmonary vascular cells. Due to limited treatment options, unravelling novel drug able signaling axis to be modulated as a therapeutic strategy is of utmost interest.The nuclear cellular compartment is a key organelle driving numerous biological processes, it is therefore important that the nuclear structural integrity is maintained to ensure its optimal functioning. Unfortunately, the nuclear structural integrity could be compromised or altered as a result of cellular stress, or mechanosensing. This has been a concept in various pathological conditions but not yet elucidated in the context of pulmonary hypertension. Thus, the aim of this study is to unravel how actin cytoskeleton can alter nuclear structure, and drive the phenotype observed in pulmonary hypertension towards novel therapeutic approach. Methods Using confocal microscopy, we profiled possible alterations in cytoskeleton and nuclear structures in IPAH patients, Hypoxic PCLS and Jasplakinolide-stimulated pulmonary arterial smooth muscle cells. In addition, we employed siRNA mediated knockdown strategy, pharmacological inhibition, gene and protein expression profiling (western blotting, immunofluorescence and qPCR) and bulk RNA-sequencing to identify key drivers and pathways involved the observed phenotype.Also, chromatin accessibility assay was used to investigate the enrichment of the signaling molecule of the predicted pathway upon actin disruption and our patients’ cohort. Finally, we studied the regulation of SUN1/ARPC5 and the effect of XMU-MP-1 (Hippo inhibitor) using Monocrotaline-induced PH rat model. Result: Our results show that Jasplakinolide induced the accumulation of SUN1 protein which correlates with increased actin related protein complex 5 (ARPC5), Loss of nuclear circularity, volume and nuclear shrinking. This same phenotype was observed in IPAH, Hypoxic PCLS and MCT-induced PH when compared with respective control groups.RNA-seq and chromatin accessibility assay inferred dysregulation of Hippo signaling and altered enrichment of Hippo molecules upon actin maneuver. Moreover, siRNA KD of SUN1/ARPC5 axis ameliorated the phenotype observed upon actin polymerization, IPAH phenotype and dysregulates hippo pathway.In vivo data using the Hippo signaling inhibitor (XMU-MP-1) attenuated PH-like phenotype, ablated the SUN1/ARPC5 axis and reduced hemodynamic alterations upon treatment.Interestingly, MCT-rats treated with XMU-MP-1 showed reduced expression of epigenetic players PCAF, and TBP upon treatment which correlates with reduced expression of key PAH signature genes. Conclusion: our data suggest actin mediated nuclear architectural alteration as a key signature driving PH and can be modulated via ARPC5/SUN1/Hippo signaling axis. Thus, a potential therapeutic option in PH.
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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 | 0.001 |
| 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".