Abstract 15163: The p110α[[Unable to Display Character: ]]Selective PI3K Inhibitor PIK75 Reverses SU5416/Hypoxia-Induced PH
Pulmonary arterial hypertension (PAH) is characterized by chronically elevated pulmonary artery pressure and pulmonary vascular resistance due to vascular remodeling in small pulmonary arteries. We previously reported that genetic ablation of the PI 3-kinase (PI3K) isoform p110α[[Unable to Display Character: ]]in smooth muscle cells (SMCs) or pharmacological inhibition of p110α prevents hypoxia-induced PH in mice.[[Unable to Display Character: ]]Here, we characterized the effects of selective p110α inhibition on growth factor-induced downstream signaling events in human PASMCs related to proliferation. Furthermore we investigated the effects of (therapeutic) p110α inhibition on disease development in the SU5416/hypoxia-induced rat model of established severe PH.
Methods: Rats were subcutaneously injected with SU5416 (20 mg/kg) and exposed to hypoxia (21 days) and normoxia (14 days). Treatment was carried out form day 21 via intraperitoneal injection of 50mg/kg of the p110α selective PI3K inhibitor PIK75 or same amounts of vehicle. RV systolic pressure (RVSP) was measured using a millar pressure catheter inserted via the jugular vein. RV hypertrophy was demonstrated as the ratio of RV weight to LV + septum weight. Additionally, starved PASMCs were pre-incubated with PIK75 and then stimulated with multiple growth factors for 16 hours or 5 minutes. Western blots were probed with various antibodies.
Results: Western blot analysis of downstream relays in growth factor stimulated hPASMCs demonstrated a profoundly reduced phosphorylation of AKT (threonine 308 and serine 473), GSK3ß and ERK in the PIK75 (300nM) exposed cells. Furthermore, expression of cyclin D1 as well as phosphorylation of Rb were prevented by PIK75.
Additionally, SU5416/hypoxia caused a robust elevation of the RVSP (81,0mmHg) which was significantly reduced by p110α inhibition (41,2mmHg). Furthermore, SU5416/hypoxia-induced RV hypertrophy was reversed.
Conclusion: These results reveal that inhibition of p110α prevents growth factor-induced signaling events leading to an increased PASMC proliferation furthermore it reverses severe PH in the SU5416/hypoxia model. Therefore, p110α inhibition may represent a capable strategy for the treatment of PAH.
Author Disclosures: E.M. Berghausen: None. A. Behringer: None. M. Vantler: None. S. Baldus: None. S. Rosenkranz: None.
- © 2014 by American Heart Association, Inc.