Abstract 16419: Epigenetic Readers: An Attractive Way to Tackle PAH and the Associated Vascular Comorbidities
Introduction: 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. We previously reported that CAD and PAH share many similarities, including vascular smooth muscle cells (VSMCs) pro-proliferative/anti-apoptotic and metabolic abnormalities. We could speculate that PAH and CAD development share many pathophysiological pathways. In cancer, the epigenetic reader Bromodomain-containing protein 4 (BRD4) increases transcription of many oncogenes contributing to the proliferative/apoptosis imbalance. Interestingly, BRD4 was shown to interact with miR-204 and NFAT, both critical players in PAH and CAD. We hypothesized that BRD4 is a central actor of VSMCs impairment contributing to vascular remodeling observed in PAH and CAD.
Method/Results: We demonstrated that remodeled distal pulmonary arteries from PAH patients exhibit a miR-204-dependent increase in BRD4 expression compared to controls (qRT-PCR, western blot, n=10-15, p<0.01). This phenotype is also observed in VSMC of remodeled coronary arteries from both PAH patients with CAD and non-PAH CAD patients compared to non-CAD patients (n=10, p<0.05). In vitro, we showed that BRD4 increases NFAT, Bcl-2 and Survivin (n=6, p<0.01) expression, triggering both proliferation (Ki67, p<0.05) and resistance to apoptosis (AnnexinV, p<0.05) while decreasing spare respiratory capacity (Seahorse XF, n=4, p<0.05) and hyperpolarizing mitochondrial membranes (TMRM, p<0.05). All these abnormalities were reversed upon BRD4 inhibition (JQ1 or siBRD4). In vivo, JQ1/siBRD4 reverses established PAH and prevents carotid stenosis in Sugen/hypoxia and carotid injury rat models respectively (n=8-10/group).
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 might represent an attractive target and since BRD4 inhibitors are presently in clinical trials further potentiates its uses in PAH.
Author Disclosures: J. Meloche: None. F. Potus: None. M. Vaillancourt: None. A. Bourgeois: None. S. Breuils-Bonnet: None. S. Provencher: None. S. Bonnet: None.
- © 2015 by American Heart Association, Inc.