Activated protein C directly activates human endothelial gelatinase A

Abstract

Angiogenesis (formation of new blood vessels) occurs in a number of diseases such as cancer and arthritis. The matrix metalloproteinase (MMP), gelatinase A, is secreted by endothelial cells and plays a vital role during angiogenesis. It is secreted as a latent enzyme and requires extracellular activation. We investigated whether activated protein C (APC), a pivotal molecule involved in the body's natural anti-coagulant system, could activate latent gelatinase A secreted by human umbilical vein endothelial cells (HUVEC). APC induced the fully active form of gelatinase A in a dose (100-300 nM)- and time (4-24 h)-responsive manner. The inactive zymogen, protein C, did not activate gelatinase A when used at similar concentrations. APC did not up-regulate membrane type 1 MMP (MT1-MMP) mRNA in HUVEC. In addition, the MMP inhibitor, 1, 10-phenanthroline (10 nM), was unable to inhibit APC-induced activation. These results suggested that MT1-MMP was not involved in the activation process. APC activation of gelatinase A occurred in the absence of cells, indicating that it acts directly. APC may contribute to the physiological/pathological mechanism of gelatinase A activation, especially during angiogenesis.