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

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.