Abstract 15487: The Catalytic PI 3-Kinase Subunit p110 alpha Represents a Promising Target to Inhibit Vascular Remodeling in Pulmonary Arterial Hypertension
Background: Pulmonary arterial hypertension (PAH) is a severe disease which is characterized by morphological changes within the vessel wall of small pulmonary vessels (“vascular remodeling”). Peptide growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) govern vascular remodeling processes via induction of proliferation and migration of vascular smooth muscle cells. Phosphoinositol 3-kinase (PI3K) is a central downstream mediator in growth factor-induced signaling events in these cells. However, the contribution of diverse PI3K isoforms in PAH is poorly understood.
Methods: We compared the effects of subtype-specific inhibitors of the catalytic PI3K subunits p110 alpha (PIK75), p110 beta (TGX221) and p110 delta (IC87114) on growth-factor induced proliferation and chemotaxis of human pulmonary arterial smooth muscle cells (hPASMC). Starved cells were stimulated with a mixture of different growth factors containing PDGF [30ng/ml], EGF [0,5ng/ml], bFGF [2ng/ml], insulin [0,5ng/ml], and FBS [5%]. Proliferation was detected using a BrdU incorporation assay, and chemotaxis was measured by a modified Boyden-chamber. Based on in vitro results, we generated SMC-specific p110 alpha knock-out mice in order to investigate the role of this PI3K subunit in hypoxia-induced pulmonary hypertension (3 weeks, 10% O2).
Results: Growth factor-induced proliferation and chemotaxis were both concentration-dependently inhibited by the p110 alpha-inhibitor PIK75 (IC50 300nM) but were unaffected by inhibition of p110 beta (TGX221 [3µM]) and p110 delta (IC87114 [3µM]). Consistently, SMCs isolated from pulmonary arteries of SMC-specific p110 alpha-deficient mice failed to proliferate in response to PDGF or FCS. Chronic hypoxia induced an elevated right ventricular systolic pressure and caused right heart hypertrophy in wild type mice, which were both diminished in SMC-specific p110 alpha knock out mice.
Conclusion: These results indicate that growth factor induced signaling in SMCs via the catalytic PI3K subunit p110alpha is essential for vascular remodeling in pulmonary hypertension and therefore represents a promising therapeutic target.
- © 2011 by American Heart Association, Inc.