Inhibition of endothelial cell migration through the down‑regulation of MMP-9 by A-kinase anchoring protein 12

Abstract

Abstract. Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix (ecM) molecules. ecM degradation is associated with tumor metastasis and angiogenesis. Therefore, the regulation of MMPs is of potential benefit in the treatment of various diseases, including cancer. a-kinase anchoring protein 12 (aKaP12) has been identified as a potential tumor suppressor. However, the function of aKaP12 as a tumor suppressor is not well understood. Herein, to determine the relationship between AKAP12 and MMP-9 in cancer, we first investigated the expression of MMP-9 under normoxic and hypoxic conditions in human fibrosarcoma cells. The expression of MMP-9 was not detected under normoxic conditions.; however, it was markedly increased under hypoxia in HT1080 cells. The effect of aKaP12 on the expression of MMP-9 was subsequently investigated. Hypoxia-induced MMP-9 mRNA expression was significantly reduced by overexpression of aKaP12, as was MMP-9 protein expression. in addition, when the aKaP12 transfectant-conditioned media (cM) were transferred into human endothelial cells, cell migration was significantly inhibited compared to the control group. notably, the inhibition of aKaP12 expression by sirna targeting aKaP12 resulted in an increase in the expression of active MMP-2 under normoxia, as well as of MMP-9. endothelial cell migration was also strongly increased by treatment with cM of sirna against aKaP12, as compared to the control group. Taken together, the results indicate that AKAP12 is involved in the regulation of endothelial cell migration through the inhibitory regulation of MMP-9 expression in tumor cells.

Absence of gravin-mediated signaling inhibits development of high-fat diet-induced hyperlipidemia and atherosclerosis

“…We found in the current report that gravin-t/t mice showed decreased MMP-9 expression in aortic sections, which could potentially explain the reduced atherosclerotic vascular remodeling and plaque formation. Activation of macrophage and increased expression of MMPs have been shown to contribute to the development of human atherosclerotic lesions (21,35). It has also been shown that overexpression of gravin downregulates the expression of MMP-9 in a carcinogenic cell line, where MMP-9 is involved in endothelial cell migration via downregulation of activator protein-1 and its transcriptional activity (35).…”

“…Activation of macrophage and increased expression of MMPs have been shown to contribute to the development of human atherosclerotic lesions (21,35). It has also been shown that overexpression of gravin downregulates the expression of MMP-9 in a carcinogenic cell line, where MMP-9 is involved in endothelial cell migration via downregulation of activator protein-1 and its transcriptional activity (35). A possible explanation for gravin's distinct roles in regulating MMPs may instead be related to the different substrates' specificities between the endothelial cell and VSMCs.…”

Quantitative proteomics reveals regulatory differences in the chondrocyte secretome from human medial and lateral femoral condyles in osteoarthritic patients

“…EPB41L2, AKAP12, FABP3, SCRN-1, CDV3 and are thus of high relevance and certainty. The A-kinase anchor protein 12 (AKAP12) has a pivotal role in regulation of cellular adhesion dynamics and is also a putative inhibitor of angiogenesis through down-regulation of MMP9 expression [54]. MMP9 inhibition through AKAP12 may thus suppress the typical hallmarks of OA in the LM scored individual i.e.…”

Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy

“…MMP can directly degrade the ECM as well as digest the BM ( Cardoso et al, 2010 ). Studies found an increased expression of MMP upon LPS treatment, which was accompanied by increased permeability of BBB ( Tilling et al, 1998 ; Yang et al, 2007 ; Vanlaere and Libert, 2009 ; Cardoso et al, 2010 ; Coisne and Engelhardt, 2011 ; Lee et al, 2011 ; Zhao et al, 2011 ; Qin et al, 2015 ).…”