Abstract 18475: Natural Killer Cell Deficient E4BP4 Knockout Mice Develop Spontaneous, Age-related Pulmonary Hypertension
BACKGROUND: There is a well-established link between pulmonary arterial hypertension (PAH) and immune dysfunction, including the impairment of circulating Natural Killer (NK) cells in PAH patients. While decidual NK cells are now recognized to play a role in vascular remodeling during pregnancy, little is known of the ability of peripheral NK cells to influence other vascular beds. We aimed to test the importance of NK deficiency to the pathogenesis of PAH using mice bearing a homozygous knockout of the E4BP4 transcription factor. E4BP4-/- mice possess normal T and B cell numbers, but are grossly deficient in circulating NK cells.
METHODS: Cardiopulmonary hemodynamics were assessed in naïve E4BP4-/- mice and wild type (WT) littermate controls by right and left heart catheterization at 3 and 9 months, as well as by echocardiography at 3, 6 and 9 months. For the Sugen-hypoxia model, 3-month-old mice were exposed to 21 days of hypoxia (10% O2) combined with 20mg/kg/week SU5416 prior to cardiopulmonary phenotyping.
RESULTS: Naïve E4BP4-/- mice exhibited normal right ventricular systolic pressures (RVSP) at 3 months, but by 9 months had developed significantly elevated RVSP when compared to WT controls (45.0+/-6.0 vs. 24.6+/-1.3 mmHg, P=0.01). This elevation was not accompanied by significant right ventricular (RV) hypertrophy or changes in left ventricular pressures. However, echocardiography did reveal a significant increase in left ventricular ejection fraction in E4BP4-/- mice versus controls (79.2+/-1.2 vs. 67.2+/-2.2%, P=0.0003). In the Sugen-hypoxia model, E4BP4-/- mice again exhibited a greater elevation of RVSP than WT controls (52.6+/-4.9 vs. 34.9+/-1.8 mmHg, P=0.007). Despite increased disease severity, E4BP4-/- mice displayed reduced RV hypertrophy (Fulton Index: 0.341+/-0.013 vs. 0.391+/-0.015, P=0.037), suggesting a potential role for NK cells in both pulmonary vascular remodeling and compensatory ventricular hypertrophy.
CONCLUSION: NK cell deficient E4BP4-/- mice develop spontaneous PAH by 9 months of age and more severe disease in the Sugen-hypoxia model. These findings implicate an important role for NK cells in the regulation of pulmonary vascular homeostasis and the pathogenesis of PAH.
Author Disclosures: S.D. Moore: None. S. Jafri: None. M. Southwood: None. H.J. Brady: None. F. Colucci: None. N.W. Morrell: None. M.L. Ormiston: None.
- © 2014 by American Heart Association, Inc.