Abstract 17118: Therapeutic Application of Type B Natriuretic Peptide Receptor With a Novel Gain-of-function Mutation in the Treatment of Pulmonary Arterial Hypertension
Introduction: Cyclic GMP (cGMP) is a ubiquitous second messenger that plays a central role in diverse physiologic processes. In humans, type B natriuretic peptide receptor (NPR-B) is one of the transmembrane guanylyl cyclases and synthesizes cGMP in response to C-type natriuretic peptide (CNP) binding. The nitric oxide/cGMP pathway has been recognized as an important therapeutic target in pulmonary arterial hypertension (PAH) and clinically approved drugs are available. However, therapeutic application of the CNP/NPR-B pathway in PAH has not been developed yet.
Methods and Results: Recently, we have reported a novel missense mutation in the NPR-B gene (2647G>A; Val 883 Met) in a family case showing overgrowth and bone anomalies.
We have found that overexpression of the mutated protein in human pulmonary artery smooth muscle cells (PASMCs) or human pulmonary artery endothelial cells (HPAECs) induced significant increase in cGMP levels compared to WT-NPR-B or GFP control in a ligand-independent manner (GFP, 0.097±0.050 pmol/L; WT-NPR-B, 0.084±0.039 pmol/L; Mut-NPR-B, 18.09±1.39 pmol/L; in PASMCs).
Overexpression of Mut-NPR-B suppressed proliferation (G0/G1 phase(%): GFP, 79±1; WT-NPR-B, 78±1; Mut-NPR-B, 82±1, S phase(%): GFP, 18±1; WT-NPR-B, 19±1; Mut-NPR-B, 15±1, G2/M phase(%): GFP, 3±0.4; WT-NPR-B, 2±0.1; Mut-NPR-B, 3±0.3) and induced apoptosis in PASMCs. However, those effects are not observed in HPAECs.
In vivo, rats treated with the combination of SU5416 and hypoxia developed pulmonary hypertension, right ventricular hypertrophy and pulmonary vascular obstructive lesions. Intratracheal administration of adenoviral vectors carrying Mut-NPR-B resulted in tendency toward an improvement in vascular remodeling as measured by medial wall thickness of pulmonary vessels compared to WT-NPR-B or GFP control (GFP, 52±13%; WT-NPR-B, 50±4%; Mut-NPR-B, 44±2 %, n=4).
Conclusion: Mutant NPR-B with a novel gain-of-function mutation induced significant increase in intracellular cGMP levels, inhibited proliferation, and induced apoptosis of human PASMCs. The CNP/NPR-B pathway may be an additional therapeutic target in the treatment of PAH.
- © 2013 by American Heart Association, Inc.