The BRD4-PLK1 Axis Drives Vascular Remodeling in PAH
O. Boucherat (Québec, Canada), E. Tremblay (Québec, Canada), S. Martineau (Québec, Canada), R. Jahagirdar (Calgary, Canada), E. Kulikowski (Calgary, Canada), S. Provencher (Québec, Canada), S. Bonnet (Québec, Canada)
Source: International Congress 2018 – Pathobiology of pulmonary hypertension
Session: Pathobiology of pulmonary hypertension
Session type: Poster Discussion
Number: 3929
Disease area: Pulmonary vascular diseases
Abstract BACKGROUND: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease, causing right heart failure and premature death. Mounting evidence points to the involvement of epigenetic changes in the pathogenesis of PAH. Indeed, as observed in cancer, overexpression of the epigenetic reader BRD4 was reported to promote PA smooth muscle cells (PASMCs) proliferation and survival in PAH. However, the molecular mechanisms underlying this effect are poorly understood. In cancer cells, BRD4 was shown to enhance PLK1 expression favoring cell proliferation and survival. Given that PAH and cancer share similarities, we hypothesize that the BRD4/PLK1 axis is critically involved in PAH.
AIM: Determine whether overexpression of the BRD4/PLK1 signaling has a detrimental function in PAH
METHODS AND RESULTS: PLK1 is significantly increased in distal PAs (IF) and isolated PASMCs (WB) from PAH patients compared to controls. We demonstrate that BRD4 up-regulation in PAH-PASMCs accounts for PLK1 overexpression (qPCR and WB). Pharmacological (BI6727) or molecular (siRNA) inhibition of PLK1 decreases viability (MTT), proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) in PAH-PASMCs. Moreover, as observed for BRD4, we provide evidence that PLK1 is increased in animal models mimicking PAH: the Sugen/Hypoxia (Su/Hx) and the monocrotaline rat as well as the SIV-infected macaque (IF). Pharmacological inhibition of BRD4 using Apabetalone (RVX-208) improves hemodynamic parameters (RVSP, mPAP), vascular remodeling (EVG) and results in diminished PLK1 expression (IF) in Su/Hx-treated rats with established PAH.
CONCLUSION: We demonstrate that the BRD4/PLK1 axis is increased in human PAH and represents a promising therapeutic target.
Rating:
You must login to grade this presentation.
Share or cite this content
Citations should be made in the following way:
O. Boucherat (Québec, Canada), E. Tremblay (Québec, Canada), S. Martineau (Québec, Canada), R. Jahagirdar (Calgary, Canada), E. Kulikowski (Calgary, Canada), S. Provencher (Québec, Canada), S. Bonnet (Québec, Canada). The BRD4-PLK1 Axis Drives Vascular Remodeling in PAH. 3929
You must login to share this Presentation/Article on Twitter, Facebook, LinkedIn or by email.
Member's Comments
Related content which might interest you:
Related content which might interest you: