Altered DNA‐Damage/BRD4 Signaling Pathways in the Lungs of Patients with Pulmonary Hypertension Can Propagate to the Coronary Vasculature and Induce Coronary Artery Disease
Bibliographic record
Abstract
Background Pulmonary arterial hypertension (PAH) is a devastating vasculopathy. Recent progress in understanding its pathogenesis led to an increase in patients’ quality of life. With ageing, PAH patients now develop comorbidities including coronary artery diseases (CAD), further challenging their therapeutic management. Interestingly, studies reported that CAD prevalence in PAH is 4 times higher (28.4%) compared to the global population (7.3%), suggesting a predisposition of the PAH population to develop CAD. We thus speculated that the activation of pathophysiological pathways in PAH contribute to CAD development in these patients. In both CAD and PAH, the inflammatory dependent pro‐proliferative/anti‐apoptotic phenotype of vascular smooth muscle cells (SMCs) is, at least in part, attributable to cytokines‐dependent activation of DNA damage signaling pathways including the epigenetic reader Bromodomain‐containing protein 4 (BRD4). We hypothesized that sustained DNA damage‐dependent BRD4 activation in the lungs of PAH patients contributes to CAD development by promoting coronary VSMC proliferation and resistance to apoptosis through a similar pathophysiological pathway Methods and Results We demonstrated in distal pulmonary arteries of PAH patients a significant increase in both DNA damage and BRD4 expression. Interestingly, coronary arteries from PAH patients, even without CAD, also exhibit increased BRD4 levels and enhanced DNA damage to a level comparable to the one observed in coronary arteries from CAD patients with no PAH (n=10–15, p<0.05). At the cellular levels, this phenotype is also observed in coronary artery SMCs (CoASMCs) of PAH and CAD patients compared to control CoASMCs (n=5, p<0.05). Proliferation (Ki67) and apoptosis (AnnexinV) assays revealed that, similarly to CAD patients’ CoASMCs (with no PAH), CoASMCs isolated from PAH patients are more proliferative (n=4, p<0.05) and resistant to apoptosis (n=4, p<0.05) in a BRD4‐dependent manner, as JQ1 (a BRD4 inhibitor) reverses this phenotype (n=4 p<0.05). Finally, we provide evidence that PAH‐CoASMCs are sensitive to TNF and IL‐6, as these cytokines further increase DNA damage (g‐H2AX) and BRD4 expression, thus promoting the proliferation/apoptosis imbalance, which may consequently lead to CAD. Interestingly, in vivo models of PAH also exhibit increased coronary artery remodeling and this process seems to be subsequent to PAH development. In a carotid injury model in MCT‐induced PAH rats, we demonstrated that BRD4 inhibition decreases neointima formation (n=4). Conclusion Comorbidities in PAH such as CAD has become a major clinical problem. Thus, targeting mechanisms implicated in both PAH and subsequent comorbidities is warranted. To this aim, we propose that BRD4 represents an attractive target and since BRD4 inhibitors are presently in clinical trials further potentiates its use in PAH. Support or Funding Information A “Fonds de recherche Québec‐Santé” scholarship to Jolyane Meloche and Canadian Institutes of Health Research grants to Dr. Bonnet supported this work.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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".