Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure
Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure
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DOI：
10.1182/blood-2007-10-117812
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发表时间：
2008-03-15
期刊：
影响因子：
20.3
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
--
作者：
Minamishima, Yoji Andrew;Moslehi, Javid;Kaelin, William G., Jr.
异源二聚体HIF转录因子的药理学活化似乎有希望作为治疗疾病的策略，例如贫血、心肌梗死和中风，其中组织缺氧是突出特征。HIF积累通常与氧的可用性有关，因为氧依赖性翻译后修饰（脯氨酰羟基化）标志着HIF α亚基的多聚泛素化和破坏。已经鉴定了三种能够催化该反应的酶（PHD1、PHD2和PHD3），尽管PHD2（也称为Egln1）似乎是细胞培养实验中主要的HIF脯氨酰羟化酶。我们发现，小鼠中PHD2的条件性失活足以激活HIF靶基因的一个子集，包括促红细胞生成素，导致红细胞生成的显著增加。缺乏PHD2的小鼠表现出与显著静脉充血和扩张型心肌病相关的过早死亡。后者可能是高粘滞综合征和容量超负荷的结果，尽管不能排除慢性高水平HIF刺激对心肌细胞的直接影响。
Pharmacologic activation of the heterodimeric HIF transcription factor appears promising as a strategy to treat diseases, such as anemia, myocardial infarction, and stroke, in which tissue hypoxia is a prominent feature. HIF accumulation is normally linked to oxygen availability because an oxygen-dependent posttranslational modification (prolyl hydroxylation) marks the HIF alpha subunit for polyubiquitination and destruction. Three enzymes (PHD1, PHD2, and PHD3) capable of catalyzing this reaction have been identified, although PHD2 (also called Egln1) appears to be the primary HIF prolyl hydroxylase in cell culture experiments. We found that conditional inactivation of PHD2 in mice is sufficient to activate a subset of HIF target genes, including erythropoietin, leading to striking increases in red blood cell production. Mice lacking PHD2 exhibit premature mortality associated with marked venous congestion and dilated cardiomyopathy. The latter is likely the result of hyperviscosity syndrome and volume overload, although a direct effect of chronic, high-level HIF stimulation on cardiac myocytes cannot be excluded.