Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption

Aya Watanabe, Toshihiro Ichiki, Chikahiro Sankoda, Yusuke Takahara, Jiro Ikeda, Eriko Inoue, Tomotake Tokunou, Shiro Kitamoto, Kenji Sunagawa

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)671-678
Number of pages8
JournalClinical Science
Volume126
Issue number9
DOIs
Publication statusPublished - May 1 2014

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Prolyl Hydroxylases
Abdominal Aortic Aneurysm
Extracellular Matrix
Inflammation
Matrix Metalloproteinases
Prolyl-Hydroxylase Inhibitors
Protein Domains
Macrophages
Cytokines
Adventitia
Chemokine CCL2
Matrix Metalloproteinase 9
Inbred C57BL Mouse
Drinking Water

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption. / Watanabe, Aya; Ichiki, Toshihiro; Sankoda, Chikahiro; Takahara, Yusuke; Ikeda, Jiro; Inoue, Eriko; Tokunou, Tomotake; Kitamoto, Shiro; Sunagawa, Kenji.

In: Clinical Science, Vol. 126, No. 9, 01.05.2014, p. 671-678.

Research output: Contribution to journalArticle

Watanabe, Aya ; Ichiki, Toshihiro ; Sankoda, Chikahiro ; Takahara, Yusuke ; Ikeda, Jiro ; Inoue, Eriko ; Tokunou, Tomotake ; Kitamoto, Shiro ; Sunagawa, Kenji. / Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption. In: Clinical Science. 2014 ; Vol. 126, No. 9. pp. 671-678.
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