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The Role of Matrix Metalloproteinases-2 and -9 in Mediating Venous Thrombus Resolution

Lornie Phillips, II¹, Erika Wong², Rajabrata Sarkar.^3
1 University of California at San Francisco - East Bay, Oakland, Calif.;²NCIRE, San Francisco, Calif.;³ University of California at San Francisco, NCIRE, San Francisco, Calif.

OBJECTIVES: The process of thrombus resolution is central to the pathogenesis of the post-thrombotic syndrome after deep venous thrombosis (DVT), although the molecular mechanisms responsible for thrombus resolution remain poorly understood. Matrix metalloproteinases are a family of proteolytic enzymes important in angiogenesis and tissue remodeling. The expression and activity of MMP-2 and MMP-9 are elevated during thrombus resolution but their specific role to thrombus resolution remains unknown. We studied the activity of MMP-2 and MMP-9 in experimental thrombus resolution and defined the role of each enzyme by studying thrombus resolution in mice with targeted deletion of each gene.

METHODS: DVT were generated by infrarenal vena caval ligation in the following groups of mice: - wildtype CD-1, mice lacking MMP-2 (MMP-2 (-/-) and their wild type littermate controls (MMP-2 (+/+), and MMP-9 knockout mice (MMP-9 (-/-) and their littermate controls (MMP-9 (+/+). Thrombus weight was analyzed at day 3 and day 12, and expressed as thrombus weight/body weight ratios. Gelatin zymography was performed for MM-2 and MMP-9 activity. Sham operations were done to control for inflammatory effects of surgery on MMP activity. Data are mean + SEM.

RESULTS: Thrombi in CD-1 wildtype mice showed an increase in MMP2 and MMP9 by zymography as compared to sham operations. Thrombi in MMP-2 (-/-) mice were similar to their wildtype controls at day 3 (thrombus/body ratio (mg/g) 0.921 + 0.259, vs. 0.88121 + 0.0963. p=0.812 by two tailed t test. n=14) but were 27% larger than their controls on day 12 (0.477 + 0.139, vs. 0.374 + 0.093. p=0.034 by two tailed t test. n=14) MMP9 thrombi were similar to their wildtype controls at day 3 (thrombus/body ratio 1.037 + 0.0683, vs. 0.925 + 0.0607. p=0.297 by two tailed t test. n=10-12) but were 31% larger than their controls on day 12 (0.511 + 0.0353, vs. 0.389 + 0.0393. p=0.031 by two tailed t test. n=12)

CONCLUSIONS: Both MMP-2 and MMP-9 activity are increased during experimental thrombus resolution. These proteins appear to play a critical role in thrombus resolution. These studies are the first to identify the specific MMP proteases responsible for thrombus resolution, and increase our understanding of the biology of this clinically important process.

AUTHOR DISCLOSURES: L. Phillips, NIH/NHLBI; E. Wong, None; R. Sarkar, NIH/NHLBI.