Abstract 12681: Implication of Aurora Kinase B in Pulmonary Arterial Hypertension

Objective: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by a progressive remodelling of pulmonary arteries (PAs). This leads to an elevation in PA pressure and resistance, leading to right heart failure and death. Nowadays, it is recognized that PA smooth muscle cells (PASMCs) are key actors in the histopathological changes in PAH. As seen in cancer cells, PASMCs exhibit a pro-proliferative and anti-apoptotic cancer-like phenotype, sustained by an important metabolic switch known as Warburg effect. Aurora kinase B (AURKB) is strongly involved in cell proliferation, apoptosis and metabolism by controlling cell cycle activation and mitochondrial functions. Previous research has shown that AURKB is overexpressed in various human cancers and its inhibition repressed tumor progression both in vivo and in vitro, suggesting that it could be a novel therapeutic target in PAH. We thus hypothesized that AURKB is upregulated in PAH and contributes to PAH-PASMCs proliferation and resistance to apoptosis, inhibition of which may reverse PA remodeling. Methods/Results: Using Western blot (WB), we demonstrated a FOXM1-dependent upregulation of AURKB in PASMCs isolated from PAH patients compared to controls (p<0.05 ; n=8-14). Similar results were found in the monocrotaline (MCT) and sugen-hypoxia (Su/Hx) rat models (p<0.05 ; n=11-22). In vitro, we found that pharmacological inhibition of AURKB significantly decreases PAH-PASMC proliferation (EdU incorporation, Ki67 labeling) as well as resistance to apoptosis (Annexin V assay) (p<0.05 ; n=6). We also demonstrated that inhibition of AURKB decreases pro-survival factors such as Survivin and PLK1 and increases apoptosis and cell cycle arrest factors including P21, P27, and P53 (WB; p<0.05 ; n=6). As expected, inhibition of AURKB in PAH-PASMCs was associated with a dose-dependent decrease of phosphohistone H3 expression, a well-known target of AURKB (p<0.05 ; n=6). The therapeutic potential of Barasertib, a clinically available and specific AURKB inhibitor, is currently investigated in both MCT and Su/Hx models. Conclusion: Our preliminary data suggests the contribution of AURKB in PA remodeling and the great potential of using AURKB inhibitors to reverse PAH development.