AMP-activated Protein Kinase Suppresses Matrix Metalloproteinase-9 Expression in Mouse Embryonic Fibroblasts

作者：Morizane Yuki; Thanos Aristomenis; Takeuchi Kimio; Murakami Yusuke; Kayama Maki; Trichonas George; Miller Joan; Foretz Marc; Viollet Benoit; Vavvas Demetrios G^*

来源：Journal of Biological Chemistry, 2011, 286(18).

DOI：10.1074/jbc.M110.199398

Matrix metalloproteinase-9 (MMP-9) plays a critical role in tissue remodeling under both physiological and pathological conditions. Although MMP-9expression 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 alpha 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 AMPK alpha deletion significantly elevated MMP-9 expression compared with wild-type (WT) MEFs, whereas single knock-out of the isoforms AMPK alpha 1 and AMPK alpha 2 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) AMPK alpha elevated MMP-9 expression. However, in AMPK alpha(-/-) MEFs transduced with DN AMPK alpha, MMP-9 expression was suppressed. AMPK alpha(-/-) MEFs showed increased phosphorylation of I kappa B alpha, expression of I kappa B alpha mRNA, nuclear localization of nuclear factor-kappa B (NF-kappa B), and DNA-binding activity of NF-kappa B compared with WT. Consistently, selective NF-kappa B inhibitors BMS345541 and SM7368 decreased MMP-9 expression in AMPK alpha(-/-) MEFs. Overall, our results suggest that both AMPK alpha isoforms suppress MMP-9 expression and that both the activity and presence of AMPK alpha contribute to its function as a regulator of MMP-9 expression by inhibiting the NF-kappa B pathway.

• 出版日期2011-5-6