Abstract 17140: Altered Epigenetic Signaling in the Coronary Arteries of Patients With Pulmonary Arterial Hypertension: the Role for BRD4 in the Development of Comorbidities
Rationale: Pulmonary arterial hypertension (PAH) is a devastating vasculopathy. Recent progress in understanding its pathogenesis led to an increase in patient’s quality of life but also to the occurrence of comorbidities including coronary artery diseases (CAD), which has a prevalence 4 times higher in PAH compared to the global population. Both CAD and PAH, are associated with a pro-proliferative/anti-apoptotic phenotype of smooth muscle cells (SMCs), attributable to inflammation-induced DNA damage signaling pathways including the Bromodomain-containing protein 4 (BRD4). We thus hypothesized that the increase in circulating cytokines like IL-6- and TNF secreted by peripheral blood mononuclear cell (PBMC) seen in PAH patients promote DNA damage/BRD4 axis activation in the coronary circulation of PAH patients triggering CAD.
Methods/Results: We demonstrated in both human and experimental models of PAH (monocrotaline & sugen rats) that PAH was associated with a significant remodeling of the coronary arteries (n=5, p<0.05) similar to CAD. Using time course we showed that CAD development parallel PAH development, suggesting that both pathologies are linked together. As seen in the distal PA, CAD in PAH patients was associated with an increase in DNA damage/BRD4 activation within the coronary artery SMCs (CoASMCs) (n=5, p<0.05). In vitro using human CoASMCs from control and PAH patients, we demonstrated that IL-6, TNF and PBMC accounting for DNA damage/Brd4 axis activation. This activation promoted control CoASMCs proliferation (Ki67) and resistance to apoptosis (annexin V) mimicking PAH-CAD, while its inhibition with BRD4 inhibitor in PAH- CoASMCs had the opposite effect (n=4, p<0.05). In vivo improvement of PAH by BRD4 inhibitor was associated with a reduction in CAD (n=5, p<0.05). Similarly, BRD4 inhibition reverses vascular remodeling in the carotid injury model (n=5, p<0.05).
Conclusions: We demonstrated in both human and experimental model that CAD is present in PAH. We provide evidence that this important comorbidity is resulting from the activation of DNA damage/ BRD4 signaling by the circulating cytokines secreted by the PBMC. Targeting this axis represent an attractive therapeutic avenue to improve PAH and the associated CAD.
Author Disclosures: V. Nadeau: Other Research Support; Significant; Actelion Pharmaceuticals Ltd. J. Meloche: None. E. Tremblay: None. M. Lampron: None. F. Potus: None. O. Boucherat: None. R. Paulin: None. E. Charbonneau: None. S. Provencher: None. S. Bonnet: None.
- © 2016 by American Heart Association, Inc.