Abstract
Background: As in cancer, pulmonary arterial hypertension (PAH) is associated with sustained DNA damage accounting for a PARP-1-dependent downregulation of miR-204. By an unknown mechanism, miR-204 promotes the expression of several oncogenes implicated in PAH including Survivin, Bcl-2, Pim-1 and c-Myc. Once activated, by affecting the mitochondrial function through the transcription factor NFAT, they contribute to the pro-proliferative and anti-apoptotic phenotype of PAH-pulmonary arterial smooth muscle cells (PASMC). In cancer, studies demonstrated that the epigenetic reader Bromodomain-containing protein 4 (BRD4) increases transcription of multiple oncogenes sustaining cell proliferation. Interestingly, BRD4 is upregulated by DNA damage and is a predicted target of miR-204. We hypothesized that the PARP-1/miR-204-dependent upregulation of BRD4 triggers the oncogenes-dependent pro-proliferative and anti-apoptotic phenotype seen in PAH-PASMC.
Method/Results: BRD4 is upregulated in lungs, distal PAs and PASMC of PAH patients compared to healthy donors. This increase is miR-204 dependent, as miR-204 upregulation in PAH-PASMC decreases BRD4. BRD4 activation induces Bcl2, Survivin, c-Myc and Pim1 expression, leading to mitochondrial hyperpolarization (TMRM) and NFAT activation in PAH-PASMC, all of which were reversed upon molecular (siRNA) and pharmacological (JQ1 and I-BET) BRD4 inhibition. Finally, BRD4 inhibition reverses PAH-PASMC proliferation (Ki67) and resistance to apoptosis (TUNEL).
Conclusion: Our study suggests an important role for BRD4 in pulmonary hypertension and opens the door to new avenues of investigation and proposes BRD4 as putative treatment for PAH.
- © 2014 ERS