Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia
Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia
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DOI：
10.2353/ajpath.2009.080345
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发表时间：
2009-03-01
影响因子：
6
通讯作者：
Miller, York E.
中科院分区：
文献类型：
--
作者：
Dempsey, Edward C.;Wick, Marilee J.;Miller, York E.
脑啡肽酶是一种跨膜金属内肽酶，其降解对生长和收缩都很重要的神经肽。除了促进致癌作用外，脑啡肽酶水平的降低还增加炎症和神经内分泌细胞增生，这可能易导致血管重塑。早期的药理学研究表明，脑啡肽酶抑制可降低慢性缺氧性肺动脉高压。我们用遗传学方法来检验另一种假设，即脑啡肽酶耗竭会增加慢性缺氧性肺动脉高压。脑啡肽酶的缺失对基线气道或肺泡壁结构、血管密度、心脏功能、红细胞压积或其他相关肽酶没有影响。只有肺神经内分泌细胞增生和微妙的神经肽失衡被发现。慢性缺氧后，neprilysin裸小鼠表现出夸张的肺动脉高压和显着增加远端血管的肌肉化。还检测到小鼠中通常未观察到的近端中膜/外膜轻微增厚。相反，适应性右心室肥大低于预期。缺氧野生型肺血管表现出密切的时间和空间关系减少脑啡肽酶和增加细胞生长。与对照组相比，无脑啡肽酶的肺动脉平滑肌细胞增殖增加，而脑啡肽酶替代降低了增殖。这些数据表明，脑啡肽酶可能是保护对慢性缺氧性肺动脉高压在肺，至少部分通过衰减平滑肌细胞的生长。肺靶向策略，以增加脑啡肽酶水平可能有治疗这种疾病的治疗效益。(Am J Pathol 2009，174：782-796; DOI：10.2353/ajpath.2009.080345）
Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition. We used a genetic approach to test the alternate hypothesis that neprilysin depletion increases chronic hypoxic pulmonary hypertension. Loss of neprilysin had no effect on baseline airway or alveolar wall architecture, vessel density, cardiac function, hematocrit, or other relevant peptidases. Only lung neuroendocrine cell hyperplasia and a subtle neuropeptide imbalance were found. After chronic hypoxia, neprilysin-null mice exhibited exaggerated pulmonary hypertension and striking increases in muscularization of distal vessels. Subtle thickening of proximal media/adventitia not typically seen in mice was also detected. In contrast, adaptive right ventricular hypertrophy was less than anticipated. Hypoxic wild-type pulmonary vessels displayed close temporal and spatial relationships between decreased neprilysin and increased cell growth. Smooth muscle cells from neprilysin-null pulmonary arteries had increased proliferation compared with controls, which was decreased by neprilysin replacement. These data suggest that neprilysin may be protective against chronic hypoxic pulmonary hypertension in the lung, at least in part by attenuating the growth of smooth muscle cells. Lung-targeted strategies to increase neprilysin levels could have therapeutic benefits in the treatment of this disorder. (Am J Pathol 2009, 174:782-796; DOI: 10.2353/ajpath.2009.080345)