Type B Human Natriuretic Peptide Receptor with a novel gain-of-function mutation provides therapeutic potential in the treatment of pulmonary arterial hypertension.

最近，我们报道了一个新的错义突变的NPR-B基因（2647 G>A;瓦尔883 Met）在一个家庭的情况下，表现出过度生长和骨畸形，我们发现，在人肺动脉平滑肌细胞（PASMCs）的突变蛋白的过度表达诱导cGMP水平显着增加相比，WT-NPR-B或GFP控制配体非依赖性的方式。过表达Mut-NPR-B可抑制PASMCs的增殖。在体内，SU 5416和缺氧联合治疗的大鼠出现肺动脉高压、右心室肥大和肺血管阻塞性病变。与WT-NPR-B或GFP对照相比，通过肺血管的中壁厚度测量，体内施用携带Mut-NPR-B的腺病毒载体导致血管重塑改善的趋势（GFP，52 ± 13%; WT-NPR-B，50 ± 4%; Mut-NPR-B，44 ± 2%，n=4）。

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) induced significant increase in cGMP levels compared to WT-NPR-B or GFP control in a ligand-independent manner. Overexpression of Mut-NPR-B suppressed proliferation in PASMCs. 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).