Author + information
- Eva Maria Berghausen,
- Wiebke Janssen,
- Marius Vantler,
- Henrik ten Freyhaus,
- Jean J. Zhao,
- Ralph T. Schermuly and
- Stephan Rosenkranz
Pulmonary arterial hypertension (PAH) is characterized by chronically elevated pulmonary artery pressure (PAP). It occurs secondary to morphological changes in the wall of pulmonary arterioles (“vascular remodelling”), which is triggerd by growth factor (GF) induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). In recent experiments we identified PI3Kα as a central downstream mediator in growth factor induced proliferation and migration of PASMCs. Therefore, we investigated whether a genetic or pharmacological inactivation of PI3Kα may prevent hypoxia-induced PH in mice.
We generated a SM-specific PI3Kα deficient mouse and subjected it to chronic hypoxia in order to induce PH. Additionally, we treated wild-type mice with the specific PI3Kα[[Unable to Display Character: ]] inhibitor PIK75 (50 mg/kg daily; i.p.) during hypoxia exposure. Controls received the same amount of vehicle. RV systolic pressure was determined via invasive measurement using millar pressure catheter. RV hypertrophy was assessed as RV/LV+septum weight ratio. Vascular remodeling was determined by morphometric analysis of vascular muscularization and medial thickness of lung tissue sections using Leica Q Win standard analyzing software.
In both approaches, ablation of PI3Kα activity significantly diminished the fraction of fully muscularized small pulmonary arteries and a narrowed medial wall thickness compared to either controls assigning SM-PI3Kα a keyfunction in hypoxia-induced vascular remodelling. Consequently, SM-specific PI3Kα deficiency or PIK75 treatment of mice led to significantly lower RV systolic pressure and RV hypertrophy compared to their corresponding controls.
These results indicate a crucial function of PI3Kα in hypoxia-induced PH. Therefore, inhibition of PI3Kα represents a promising strategy for the treatment of PAH.
Poster Sessions, Expo North
Monday, March 11, 2013, 9:45 a.m.-10:30 a.m.
Session Title: Pulmonary Hypertension: Pre-Clinical, Clinical, Biomarkers
Abstract Category: 27. Pulmonary Hypertension
Presentation Number: 1294-149
- 2013 American College of Cardiology Foundation