Roles of Brd4 in Vascular Smooth Muscle Cells: Implications for Aging and Vascular Dysfunction
Bibliographic record
Abstract
BACKGROUND: Growing evidence suggests that the epigenetic reader Brd4 (bromodomain-containing protein 4) is involved in aging and aging-related diseases. However, the specific mechanisms by which Brd4 influences vascular aging, especially senescence of vascular smooth muscle cells (SMCs), remain unexplored. METHODS: Primary cell cultures were established using mouse aortic SMCs and treated with Brd4 inhibitor, ARV-825, or (+)-JQ1. Primary Brd4 flox/flox mouse aortic SMCs were transduced with Ad-Cre virus to induce Brd4 knockout (KO). Senescence was assessed through SA-β-gal (senescence-associated β-galactosidase) staining. A mouse model of inducible SMC-specific Brd4 gene KO (SMC-Brd4-KO) was generated with the Cre-LoxP system. The control and SMC-Brd4-KO mice were evaluated for arterial contractility, blood pressure, arterial stiffness, and Ang II (angiotensin II)–induced vascular aging, as well as transcriptome profiling using RNA-sequencing analysis. RESULTS: Brd4 inhibition with ARV-825, (+)-JQ1, or Brd4 knockdown through Ad-Cre virus in Brd4 flox/flox SMCs led to cellular senescence. Induced SMC-Brd4-KO in adult mice prevented neointima formation. SMC-Brd4-KO mice exhibited increased aortic stiffness and blood pressure with enhanced arterial contractility ex vivo. In addition, Brd4 expression was downregulated in aortic tissues of aged mice and senescent human aortic SMCs. Furthermore, SMC-Brd4-KO mice displayed more prominent histopathologic features of vascular aging in response to Ang II infusion. Aortic tissues from SMC-Brd4-KO mice showed a more robust contractile response to Ang II and phenylephrine, accompanied by multiple genetic changes, including alterations in cytoskeleton genes. Transcriptomes of Brd4 KO aortas displayed gene signatures of dampened autophagy, intriguingly associated with a downregulation of microtubule genes, including Tuba4a (α-tubulin). Experiments in vitro with Brd4 KO SMCs demonstrated the potential role of impaired autophagy and depleted α-tubulin in mediating induction of senescence in SMCs. CONCLUSIONS: Brd4 depletion in SMCs induces senescence, prevents neointima formation, and exacerbates vascular aging, highlighting its crucial roles in vascular functions and diseases.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".