Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease.
Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease.
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临床和实验性主动脉瘤疾病中缺氧诱导因子1。
DOI：
10.1016/j.jvs.2017.09.030
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发表时间：
2018-11
影响因子：
4.3
通讯作者：
Dalman RL
中科院分区：
文献类型：
--
作者：
Wang W;Xu B;Xuan H;Ge Y;Wang Y;Wang L;Huang J;Fu W;Michie SA;Dalman RL
壁血管生成和巨噬细胞积聚是腹主动脉瘤（AAA）疾病的两个病理标志。低氧诱导因子（hypoxia inducible factor，HIF）-1是一种异源二聚体转录因子，是血管生成和巨噬细胞功能的重要调节因子。在这项研究中，我们调查了HIF-1的表达和活性在临床和实验性AAA疾病。在开腹手术期间从24名AAA患者和6名器官供体获得人主动脉样品。在10周龄雄性C57 BL/6 J小鼠中通过猪胰腺弹性蛋白酶的瞬时主动脉内输注产生实验AAA。检测HIF-1α及其靶基因mRNA在垂体瘤和对照垂体瘤中的表达。在猪胰弹性蛋白酶输注之前或之后的不同时间点，每天向小鼠给予HIF-1α抑制剂2-甲氧基紫杉醇或地高辛，或含脯氨酰羟化酶结构域的蛋白抑制剂氯化钴和JNJ-42041935，或单独给予溶剂作为对照。通过一系列经腹超声评估主动脉直径和处死时的组织病理学分析来评估对实验性AAA形成和进展的影响。HIF-1α、血管内皮生长因子A、葡萄糖转运蛋白1和基质金属蛋白酶2的mRNA水平在人和实验性动脉瘤组织中均显著升高。组织免疫染色检测到更多的HIF-1α蛋白在人类和实验性垂体，与各自的控制垂体。在猪胰弹性蛋白酶输注之前或之后开始使用HIF-1α抑制剂治疗，可防止实验性动脉瘤扩大。两种HIF-1α抑制方案均减弱了中膜弹性蛋白降解、平滑肌细胞耗竭、壁血管生成以及巨噬细胞、T细胞和B细胞的积聚。虽然含脯氨酰羟化酶结构域蛋白（PHD）1和PHD 2的mRNA水平在实验性动脉瘤中升高，但PHD的药理学抑制对实验性动脉瘤进展的影响有限。HIF-1α及其靶基因在人和实验性AAA中的表达增加。HIF-1α抑制剂治疗限制了实验性AAA进展，组织学证据表明壁白细胞浸润和血管生成减弱。这些发现强调了HIF-1α在动脉瘤发病机制中的潜在意义，并作为药物抑制AAA疾病的靶点。
Mural angiogenesis and macrophage accumulation are two pathological hallmarks of abdominal aortic aneurysm (AAA) disease. The heterodimeric transcription factor, hypoxia inducible factor (HIF)-1, is an essential regulator of angiogenesis and macrophage fucntion. In this study we investigated HIF-1 expression and activity in clinical and experimental AAA disease. Human aortic samples were obtained from 24 AAA patients and six organ donors during open abdominal surgery. Experimental AAAs were created in 10 weeks old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase. Expression of HIF-1α and its target gene mRNA levels were assessed in aneurysmal and control aortae. The HIF-1α inhibitors 2-methoxyestradiol or digoxin, or the prolyl-hydroxylase domain-containing protein inhibitors cobalt chloride and JNJ-42041935, or vehicle-alone as control, were administered daily to mice at varying timing points beginning before or after porcine pancreatic elastase infusion. Influences on experimental AAA formation and progression were assessed via serial transabdominal ultrasonographic assessment of aortic diameter and histopathologic analysis at sacrifice. mRNA levels for HIF-1α, vascular endothelial growth factor-A, glucose transporter-1 and matrix metalloproteinase 2 were significantly increased in both human and experimental aneurysm tissue. Tissue immunostaining detected more HIF-1α protein in both human and experimental aneurysmal, as compared to respective control aortae. Treatment with either HIF-1α inhibitor, beginning either before or after porcine pancreatic elastase infusion, prevented enlargement of experimental aneurysms. Both HIF-1α inhibition regimens attenuated medial elastin degradation, smooth muscle cell depletion, mural angiogenesis, and the accumulation of macrophages, T cells and B cells. While mRNA levels for prolyl-hydroxylase domain-containing protein (PHD) 1 and PHD 2 were elevated in experimental aneurysmal aortae, pharmacological inhibition of PHDs had limited effect on experimental aneurysm progression. Expression of HIF-1α and its target genes are increased in human and experimental AAAs. Treatment with HIF-1α inhibitors limits experimental AAA progression, with histologic evidence of attenuated mural leukocyte infiltration and angiogenesis. These findings underscore the potential significance of HIF-1α in aneurysm pathogenesis and as a target for pharmacologic suppression of AAA disease.
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影响因子：
4.6
作者：
Daijo H;Hoshino Y;Kai S;Suzuki K;Nishi K;Matsuo Y;Harada H;Hirota K
通讯作者：
Hirota K
影响因子：
50.3
作者：
Mabjeesh, NJ;Escuin, D;Giannakakou, P
通讯作者：
Giannakakou, P
影响因子：
64.5
作者：
Dang EV;Barbi J;Yang HY;Jinasena D;Yu H;Zheng Y;Bordman Z;Fu J;Kim Y;Yen HR;Luo W;Zeller K;Shimoda L;Topalian SL;Semenza GL;Dang CV;Pardoll DM;Pan F
通讯作者：
Pan F
影响因子：
4.3
作者：
Mayranpaa, Mikko I.;Trosien, Julia A.;Hedin, Ulf
通讯作者：
Hedin, Ulf
影响因子：
4.3
作者：
Kent, K. Craig;Zwolak, Robert M.;Greco, Giampaolo
通讯作者：
Greco, Giampaolo