大動脈解離(AAD)患者ではMMP9血中濃度が上昇し, 患部血管手術標本ではMMP9が好中球と一致して上昇していた。BAPNを前投与したマウスにAngIIを投与してAADを惹起させるマウスモデルの検討から, MMP9阻害剤投与でAAD発症率が低下し, MMP9ノックアウトマウスではAADがほぼ完全に抑制された。好中球除去もAADの発症は減少した。AAD患部血管では酸化ストレスが有意に亢進し, 酸化ストレス阻害剤投与でマウスAAD発症率とMMP9産生が減少した。血管平滑筋細胞と好中球の共培養から, 血管平滑筋細胞をAngIIで刺激すると好中球のMMP9産生が亢進し, 酸化ストレス阻害剤で抑制された。
We found MMP9 was elevated significantly in blood samples from acute aortic dissection (AAD) patients. Using a novel AAD model by infusing angiotensin II to immature mice that had been received a lysyl oxidase inhibitor, we found the incidence of AAD was reduced significantly following the administration of an MMP inhibitor and was almost blocked completely in MMP9 (-/-) mice. Neutrophil depletion also significantly decreased the incidence of AAD. Oxidative stress is upregulated in the AAD aorta and an oxidative stress inhibitor reduced the incidence of AAD and the production of MMP9. Coculture experiments using vascular smooth muscle cells and neutrophils revealed the upregulation of MMP9 by neutrophils following AngII stimulation of VSMCs, which was blocked by ROS inhibitor. These data suggest that AAD is initiated by neutrophils that have infiltrated the aortic intima and released MMP9 in response to angiotensin II and the following oxidative stress upregulation.

研究種目 : 若手研究(B)
研究期間 : 2013～2015
課題番号 : 25870718
研究分野 : 血管医学