Morizane, Y.Thanos, AristomenisTakeuchi, K.Murakami, Y.Kayama, M.Trichonas, G.Miller, JoanForetz, M.Viollet, B.Vavvas, Demetrios2018-04-102011Morizane, Y., A. Thanos, K. Takeuchi, Y. Murakami, M. Kayama, G. Trichonas, J. Miller, M. Foretz, B. Viollet, and D. G. Vavvas. “AMP-Activated Protein Kinase Suppresses Matrix Metalloproteinase-9 Expression in Mouse Embryonic Fibroblasts.” Journal of Biological Chemistry 286 (18) (2011): 16030–16038.0021-9258http://nrs.harvard.edu/urn-3:HUL.InstRepos:35440079Matrix metalloproteinase-9 (MMP-9) plays a critical role in tissue remodeling under both physiological and pathological conditions. Although MMP-9 expression is low in most cells and is tightly controlled, the mechanism of its regulation is poorly understood. We utilized mouse embryonic fibroblasts (MEFs) that were nullizygous for the catalytic α subunit of AMP-activated protein kinase (AMPK), which is a key regulator of energy homeostasis, to identify AMPK as a suppressor of MMP-9 expression. Total AMPKα deletion significantly elevated MMP-9 expression compared with wild-type (WT) MEFs, whereas single knock-out of the isoforms AMPKα1 and AMPKα2 caused minimal change in the level of MMP-9 expression. The suppressive role of AMPK on MMP-9 expression was mediated through both its activity and presence. The AMPK activators 5-amino-4-imidazole carboxamide riboside and A769662 suppressed MMP-9 expression in WT MEFs, and AMPK inhibition by the overexpression of dominant negative (DN) AMPKα elevated MMP-9 expression. However, in AMPKα(-/-) MEFs transduced with DN AMPKα, MMP-9 expression was suppressed. AMPKα(-/-) MEFs showed increased phosphorylation of IκBα, expression of IκBα mRNA, nuclear localization of nuclear factor-κB (NF-κB), and DNA-binding activity of NF-κB compared with WT. Consistently, selective NF-κB inhibitors BMS345541 and SM7368 decreased MMP-9 expression in AMPKα(-/-) MEFs. Overall, our results suggest that both AMPKα isoforms suppress MMP-9 expression and that both the activity and presence of AMPKα contribute to its function as a regulator of MMP-9 expression by inhibiting the NF-κB pathway.en-USJournal Article2013-09-06Yuki Morizane, Aristomenis Thanos, Kimio Takeuchi, Yusuke Murakami, Maki Kayama, George Trichonas, Joan Miller, Marc Foretz, Benoit Viollet, and Demetrios G Vavvas10.1074/jbc.M110.199398