Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption.
Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption.
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DOI：
10.1042/cs20130435
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发表时间：
2014-05
期刊：
影响因子：
6
通讯作者：
Aya Watanabe;T. Ichiki;Chikahiro Sankoda;Yusuke Takahara;Jiro Ikeda;Eriko Inoue;T. Tokunou;S. Kitamo
中科院分区：
文献类型：
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作者：
Aya Watanabe;T. Ichiki;Chikahiro Sankoda;Yusuke Takahara;Jiro Ikeda;Eriko Inoue;T. Tokunou;S. Kitamo
在本研究中，我们试图确定氯化钴，PHD（脯氨酰羟化酶结构域蛋白）的抑制剂，对AAA（腹主动脉瘤）的发展的影响。C57 BL/6小鼠腹主动脉周围注射CaCl 2诱导AAA（AAA组）。将NaCl（0.9%）处理的小鼠用作假手术对照（SHAM组）。AAA/CoCl 2组：饮用含0.05%CoCl 2的水。术后1周和6周，切除主动脉组织进行进一步检查。CaCl 2治疗6周后，AAA组的主动脉直径和主动脉外膜中的巨噬细胞浸润与SHAM组相比增加。与AAA组相比，CoCl 2治疗减少了动脉瘤的大小和巨噬细胞浸润。AAA组主动脉炎性细胞因子和单核细胞趋化蛋白-1（MCP-1）表达增强，基质金属蛋白酶-9（MMP-9）和MMP-2活性增强，AAA/CoCl 2组主动脉炎性细胞因子和MCP-1表达减弱。CaCl 2处理1周后细胞因子的表达和MMPs的活性已经增加，但CoCl 2处理与NF-κB（核因子B）磷酸化减少相关，抑制了细胞因子的表达和MMPs的活性。在小鼠中用CoCl 2治疗防止了CaCl 2诱导的AAA的发展，并减少了炎症和ECM（细胞外基质）破坏。本研究的结果表明，PHD在AAA的发展中起着关键作用，并且PHD抑制剂在预防AAA发展中具有治疗潜力。
In the present study we sought to determine the effect of CoCl2, an inhibitor of PHD (prolyl hydroxylase domain protein), on the development of AAA (abdominal aortic aneurysm). AAA was induced in C57BL/6 mice by periaortic application of CaCl2 (AAA group). NaCl (0.9%)-treated mice were used as a sham control (SHAM group). Mice were treated with 0.05% CoCl2 in the drinking water (AAA/CoCl2 group). At 1 and 6 weeks after the operation, aortic tissue was excised for further examination. After 6 weeks of CaCl2 treatment, aortic diameter and macrophage infiltration into the aortic adventitia were increased in the AAA group compared with the SHAM group. Treatment with CoCl2 reduced the aneurysmal size and macrophage infiltration compared with the AAA group. Aortic expression of inflammatory cytokines and MCP-1 (monocyte chemoattractant protein-1) and the activities of MMP-9 (matrix metalloproteinase-9) and MMP-2 were enhanced in the AAA group and attenuated in the AAA/CoCl2 group. Expression of cytokines and the activities of MMPs were already increased after 1 week of CaCl2 treatment, but were suppressed by CoCl2 treatment in association with reduced NF-κB (nuclear factor κB) phosphorylation. Treatment with CoCl2 in mice prevented the development of CaCl2-induced AAA in association with reduced inflammation and ECM (extracellular matrix) disruption. The results of the present study suggest that PHD plays a critical role in the development of AAA and that there is a therapeutic potential for PHD inhibitors in the prevention of AAA development.