Abstract 14786: Protein Kinase G mediates Hyperoxia-Induced Vascular Changes in Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension
Introduction: Bronchopulmonary dysplasia (BPD) is a complication of prematurity and is often associated with pulmonary hypertension (PH). Protein Kinase G (PKG) is a kinase that phosphorylates multiple cellular targets leading to alterations in the perinatal vascular tone. Little is known about the role of PKG in BPD-associated PH.
Hypothesis: To elucidate the role of PKG in the context of BPD-associated PH
Methods: PKG has two possible modes of activation - cGMP or oxidative stress. We utilized global PKG knockout mice (PKG KO) and redox-dead PKG mice (C42S) which cannot be activated by oxidative stress, but maintain cGMP activation. For our hyperoxia-induced lung injury mouse model, age-matched litters of PKG KO or C42S mice were placed in room air (control) or 75% O2 (chronic hyperoxia, CH) within 24h of birth. After 14d, right ventricular hypertrophy (RVH) was measured by Fulton’s index (right ventricle/left ventricle+septum). Lungs were inflation fixed with 4% formalin and stained to measure alveolar area, pulmonary artery medial wall thickness (MWT) and vascularization by von Willebrand factor staining. Additionally, primary pulmonary artery smooth muscle cells (PASMC) were isolated from both mouse strains, placed in 21% or 95% O2 for 24h, and analyzed for phosphodiesterase5 (PDE5) activity.
Results: Isogenic wild-type (WT) control mice developed significant RVH in CH, whereas CH PKG KO and C42S mice did not develop RVH. Isogenic WT mice developed significantly increased MWT and decreased vascularization, but PKG KO and C42S mice were protected from vascular injury. However, all CH mice had significantly increased alveolar area. Isogenic WT PASMC had significantly increased PDE5 activity after 24h of 95% O2, but PKG KO and C42S PASMC did not.
Conclusions: Global loss of PKG and loss of redox-activated PKG protected from hyperoxia-induced right ventricular hypertrophy, vascular remodeling and decreased vascularization that were observed with CH WT mice as well as hyperoxia-induced PDE5 activity in PASMC. However, PKG does not appear to play a role in hyperoxia-induced alveolar simplification. Thus, modulation of redox-activated PKG activity may represent a novel new therapeutic target for BPD-associated PH.
Author Disclosures: K. Lee: None. G.A. Kim: None. J.M. Taylor: None. F. Hofmann: None. K.N. Farrow: None.
- © 2014 by American Heart Association, Inc.