Induction of Timp1 in Smooth Muscle Cells during Development of Abdominal Aortic Aneurysms
k6246_3.pdf 540 KB
k6246_1.pdf 231 KB
k6246_2.pdf 155 KB
Abdominal aortic aneurysm
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.
Batmunkh Bumdelger, Hiroki Kokubo, Ryo Kamata, Masayuki Fujii, Mari Ishida, Takafumi Ishida and Masao Yoshizumi; Induction of Timp1 in Smooth Muscle Cells during Development of Abdominal Aortic Aneurysms; Hiroshima J. Med. Sci. Vol.62, No.3, 63-67, September, 2013
Philosophy in Medical Science