Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling.
Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling.
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DOI：
10.1161/jaha.113.000178
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发表时间：
2013-06-18
影响因子：
5.4
通讯作者：
Sunagawa K
中科院分区：
文献类型：
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作者：
Ikeda J;Ichiki T;Matsuura H;Inoue E;Kishimoto J;Watanabe A;Sankoda C;Kitamoto S;Tokunou T;Takeda K;Fong GH;Sunagawa K
高血压导致心血管肥大和纤维化。浸润的巨噬细胞在这一过程中起关键作用。我们最近报道了脯氨酰羟化酶结构域蛋白2（PHD 2）的抑制，其羟化缺氧诱导因子α（HIF-α）的脯氨酸残基，从而诱导HIF-α降解，抑制巨噬细胞中的炎症反应。我们研究了髓系特异性Phd 2缺失是否影响高血压诱导的心血管重构。通过将Phd 2-floxed小鼠与LysM-Cre转基因小鼠杂交产生骨髓特异性PHD 2-缺陷小鼠（MyPHD 2KO），导致HIF-1α和HIF-2α在巨噬细胞中蓄积。给予8至10周龄的小鼠NG-硝基-L-精氨酸甲酯（L-NAME）（一种一氧化氮合酶抑制剂）和血管紧张素II（Ang II）输注。L-NAME/Ang II可增加对照组和MyPHD 2KO小鼠的收缩压。然而，MyPHD 2KO小鼠显示主动脉中膜和外膜增厚以及巨噬细胞浸润较少。MyPHD 2KO小鼠的心脏间质纤维化和心肌细胞肥大也显著改善。MyPHD 2KO小鼠的主动脉和心脏中转化生长因子-β和胶原蛋白表达降低。超声心动图分析显示，在MyPHD 2KO小鼠中未观察到对照小鼠中L-NAME/Ang II治疗诱导的左心室肥大和射血分数降低。对L-NAME/Ang II处理的MyPHD 2KO小鼠给予抑制HIF-α合成的地高辛逆转了这些有益特征。髓系中的Phd 2缺失可减轻高血压心血管肥大和纤维化，这可能是由巨噬细胞中炎症和纤维化相关基因表达减少介导的。髓系PHD 2在高血压心血管重构中起关键作用。
Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia‐inducible factor‐α (HIF‐α) and thereby induces HIF‐α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid‐specific Phd2 deletion affects hypertension‐induced cardiovascular remodeling. Myeloid‐specific PHD2‐deficient mice (MyPHD2KO) were generated by crossing Phd2‐floxed mice with LysM‐Cre transgenic mice, resulting in the accumulation of HIF‐1α and HIF‐2α in macrophage. Eight‐ to ten‐week‐old mice were given NG‐nitro‐L‐arginine methyl ester (L‐NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L‐NAME/Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor‐β and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L‐NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF‐α synthesis to L‐NAME/Ang II‐treated MyPHD2KO mice reversed these beneficial features. Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation‐ and fibrosis‐associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.