Differential Effects of Shear Stress and Cyclic Strain on Sp1 Phosphorylation by Protein Kinase Cζ Modulates Membrane Type 1–Matrix Metalloproteinase in Endothelial Cells

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Abstract
Membrane type 1–matrix metalloproteinase (MT1-MMP) plays a key role in extracellular matrix remodeling, endothelial cell (EC) migration, and angiogenesis. Whereas cyclic strain (CS) increases MT1-MMP expression, shear stress (SS) decreases MT1-MMP expression. The aim of this study was to determine if changes in levels of Sp1 phosphorylation induced by protein kinase Cζ (PKCζ) in ECs exposed to SS but not CS are important for MT1-MMP expression. The results showed that SS increased Sp1 phosphorylation, which could be inhibited by pretreatment with PKCζ inhibitors. In the presence of PKCζ inhibitors, the SS-mediated decrease in MT1-MMP protein expression was also abolished. These data demonstrate that increased affinity of Sp1 for MT1-MMP's promoter site occurs as a consequence of PKCζ-induced phosphorylation of Sp1 in response to SS, increasing Sp1 binding affinity for the promoter site, preventing Egr-1 binding, and consequently decreasing MT1-MMP expression.