Abstract 13027: Periostin Cre-mediated Hypoxia-inducible Transfroming Growth Factor-β Receptor Deletion in Pulmonary Artery Attenuates the Progression of Pulmonary Arterial Hypertension in Mice
Introduction: Mutations in the bone morphogenetic protein type II receptor, transforming growth factor-β (TGF-β) receptor superfamily member, are responsible for heritable pulmonary arterial hypertension (PAH). Although this mutation is associated with TGF-β signal activation, the precise role of TGF-β signaling still remains uncertain in pathogenesis of PAH. Under hypoxic condition, Periostin(Pn) which usually expresses in fibroblasts protein has been shown to express on vascular smooth muscle cell. Therefore, Pn-Cre-loxP system may work as conditional inhibition in hypoxic pulmonary arterial smooth muscle cells.
Methods: We established TGF-β type I receptor knockout mice specifically in periostin expressing cell (PnCre/Alk5flox model mice). A mouse model of hypoxia-induced PAH was used for this study. We evaluated right ventricular systolic pressure, function, hypertrophy, and vascular remodeling of pulmonary artery after 3 weeks of exposure to 10% of oxygen.
Results: Those mice were induced proliferation of pulmonary arterial smooth muscle cells and perivascular fibrotic change, causing pulmonary hypertension. Right ventricular pressure measured by pressure catheter was significantly decreased in PnCreAlk5flox model mice compared with wild-type mice (44.8±7.8 vs 55.0±9.7mmHg, p<0.05). Right ventricular function and right ventricular weight showed no significant difference between both mice. Histological analysis revealed inhibition of medial thickening of pulmonary artery and perivascular fibrotic change in PnCreAlk5flox model mice compared with wild-type mice (% muscularization of pulmonary artery ; 52.0±14.3 vs 78.4±11.5%, p<0.05).
Conclusions: These results indicate that TGF-β signaling in fibroblasts and smooth muscle cells has a critical role on pathogenesis of PAH, suggesting the usefulness of therapy by targeting TGF-β signaling.
Author Disclosures: M. Seki: None. N. Koitabashi: None. H. Arakawa: None. M. Kurabayashi: None.
- © 2014 by American Heart Association, Inc.