腹部大動脈瘤形成における、平滑筋細胞でのTimp1遺伝子誘導

Abdominal aortic aneurysm (AAA) is known to develop mainly by the increased diameter of aorta through metalloproteinases (MMPs). Although activities of MMPs are tightly regulated by the presence of tissue inhibitor of MMPs (TIMPs) and imbalances between MMPs and TIMPs may serve to fragility of arterial wall, little is known about TIMPs behavior in aneurysmal formation. Here, we utilized a murine experimental AAA model, and found that by immunohistochemical analysis, Timp1 as and Timp1 mRNA levels was also revealed in aortic tissue in AAA by RT-PCR. In cultured vascular smooth muscle cells (SMCs), Tumor Necrosis Factor (TNF)-α significantly activated both Mmp9 and Timp1 expression, and they were blocked by Jun kinase inhibitor (SP600125) in a dose-dependent manner. Interestingly, a proteasome inhibitor (MG132), which is known as an agent for inhibition of the nuclear factor-kappa B (NF-kB), significantly inhibited the TNF-α-induced expression of Timp1, whereas MG132, which also works as an activator of c-Jun/AP-1 pathway, strongly increased Mmp9. Taken together, inflammatory cytokines, including TNF-α, may simultaneously induce MMPs and TIMPs for the remodeling of the medial layer, leading to the increased diameter of the aorta, the aneurysm.広島大学(Hiroshima University)博士(医学)Philosophy in Medical Sciencedoctora