title: Induction of Timp1 in smooth muscle cells during development of abdominal aortic aneurysms.
abstract: 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)-alpha 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-kappaB), significantly inhibited the TNF-alpha-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-alpha, may simultaneously induce MMPs and TIMPs for the remodeling of the medial layer, leading to the increased diameter of the aorta, the aneurysm.
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Batmunkh
authors.initials: B
authors.lastname: Bumdelger
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kokubo
authors.forename: Ryo
authors.initials: R
authors.lastname: Kamata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujii
authors.forename: Mari
authors.initials: M
authors.lastname: Ishida
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ishida
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshizumi
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D002122:Calcium Chloride; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D002122:Calcium Chloride