NOD2 deficiency exacerbates hypoxia-induced pulmonary hypertension and enhances pulmonary vascular smooth muscle cell proliferation

Abstract

Expression of nucleotide-binding oligomerization domain protein 2 (NOD2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia. To investigate the involvement of NOD2 in the pulmonary vascular response to hypoxia, we subjected wild-type and NOD2-deficient mice to chronic normobaric hypoxic conditions. Compared to wild-type mice, NOD2-deficient mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, profound right ventricular hypertrophy and striking vascular remodeling after exposure to hypoxia. Pulmonary vascular remodeling in NOD2-deficient mice was characterized by increased PASMC proliferation. Furthermore, hypoxia-inducible factor-1α expression and Akt phosphorylation were upregulated in PASMCs from NOD2-deficient mice exposed to hypoxia. Our findings revealed that the absence of NOD2 exacerbated hypoxia-induced PASMC proliferation, pulmonary hypertension and vascular remodeling, but had no effect on PASMC migration or contractility.