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(Circulation Research. 2002;90:784.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Regulation of Endothelial Matrix Metalloproteinase-2 by Hypoxia/Reoxygenation

Yaara Ben-Yosef, Nitza Lahat^*, Sarah Shapiro, Haim Bitterman, Ariel Miller^*

From The Neuroimmunology Unit (Y.B.-Y., A.M.), Immunology Research Unit (Y.B.-Y., N.L., S.S.), and the Department of Internal Medicine A (H.B.), Carmel Medical Center; the Faculty of Medicine (N.L., H.B., A.M.), Technion-Israel Institute of Technology; and the Rappaport Institute for Research in Medical Science (H.B., A.M.), Haifa, Israel.

Correspondence to Ariel Miller, MD, PhD, The Neuroimmunology Unit, Department of Neurology, Carmel Medical Center, 7 Michal St, Haifa 34362, Israel. E-mail millera{at}tx.technion.ac.il

Among the consequences resulting from the exposure of endothelial cells (ECs) to ischemia/reperfusion is angiogenesis, involving degradation of vascular basement membrane and extracellular matrix. Matrix metalloproteinase (MMP)-2, a member of the MMP family, partakes in this process. MMP-2, secreted as a proenzyme, undergoes activation through interaction with membrane type (MT)1-MMP and the endogenous tissue inhibitor of MMPs (TIMP)-2. Although hypoxia and reoxygenation (H/R) are major constituents of ischemia/reperfusion processes, their direct effects on endothelial MMP-2 have been scarcely investigated. This study examined the in vitro effects of H/R on human macrovascular ECs (EAhy 926). The level of MMP-2 mRNA (Northern blot) and protein (zymography, ELISA) and the mRNA of its activator (MT1-MMP) and inhibitor (TIMP-2) were analyzed. Short (6-hour) hypoxia inhibited the mRNA expression of MMP-2, MT1-MMP, and TIMP-2, culminating in reduced latent and active MMP-2 protein. Prolonged (24-hour) hypoxia further suppressed MT1-MMP and TIMP-2 mRNA, whereas it enhanced MMP-2 mRNA and enzyme secretion (after 48-hour hypoxia). Reoxygenation did not influence the inhibited TIMP-2 but upregulated MMP-2 and MT1-MMP mRNA expression, leading to enhanced secretion of active MMP-2 protein. These results demonstrate H/R-mediated modulation of EC MMP-2 at both transcriptional and posttranscriptional levels. Prolonged hypoxia of ECs appears to enhance MMP-2 production and secretion, whereas reoxygenation further increases its level. These H/R-mediated effects on MMPs have the potential of enabling EC migration and possible angiogenesis.

Key Words: endothelium • hypoxia • reoxygenation • matrix metalloproteinases • tissue inhibitors of matrix metalloproteinases

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