The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice
The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice
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DOI：
10.1172/jci36362
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Simon, M. Celeste
中科院分区：
文献类型：
--
作者：
Hickey, Michele M.;Richardson, Theresa;Simon, M. Celeste
von Hippel-Lindau （VHL）肿瘤抑制蛋白密码子200 （R200W）的突变与Chuvash红细胞增多症有关。除了红细胞增多症外，Chuvash患者还有肺动脉高压和呼吸频率增高，尽管这些症状的病理生理基础尚不清楚。在这里，我们试图通过研究R200W Vhl突变的小鼠纯合子（Vhl（R/R）小鼠）作为Chuvash病的模型来解决这个问题。这些小鼠独立于红细胞增多症发展为肺动脉高压，并与Chuvash患者相似地增强了常氧呼吸，进一步验证了Vhl（R/R）小鼠作为Chuvash疾病的模型。Vhl（R/R）小鼠肺表现为肺血管重构、出血、水肿和巨噬细胞浸润，老年小鼠肺也表现为纤维化。HIF-2 α在Vhl（R/R）小鼠肺中的活性增加，Hif2 α的杂合性普遍抑制Vhl（R/R）小鼠的红细胞增多症和肺动脉高压，但Hif1 α没有。此外，在Vhl（R/R）肺中，Hif2 α的杂合性导致了对血管重塑、出血和水肿的部分保护，而不是炎症，这表明HIF-2 α在肺病理中的选择性作用，从而为肺动脉高压的机制提供了新的见解。这些发现有力地支持了Chuvash表型对HIF-2 α的依赖性，并提示了Chuvash患者的潜在治疗方法。
Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (Vhl(R/R) mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating Vhl(R/R) mice as a model for Chuvash disease. Lungs from Vhl(R/R) mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2 alpha activity was increased in lungs from Vhl(R/R) mice, and heterozygosity for Hif2 alpha, but not Hif1 alpha, generically suppressed both the polycythemia and pulmonary hypertension in the Vhl(R/R) mice. Furthermore, Hif2 alpha heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in Vhl(R/R) lungs, suggesting a selective role for HIF-2 alpha in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2 alpha and suggest potential treatments for Chuvash patients.