[Frontiers in Bioscience 11, 3121 -3128, September 1, 2006]

MMP-9 expression is associated with leukocytic but not endothelial markers in brain arteriovenous malformations

Yongmei Chen 1, Yongfeng Fan 1, K. Y. Trudy Poon 1, Achal S. Achrol 1, Michael T. Lawton 2, Yiqian Zhu 1, Charles E McCulloch 4, Tomoki Hashimoto 1, Chanhung Lee 1, Nicholas M. Barbaro 2, Andrew W. Bollen 5, Guo-Yuan Yang 1,2, and William L. Young 1, 2, 3

1 Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, Departments of 2 Neurological Surgery, 3 Neurology, 4 Epidemiology and Biostatistics, and 5 Pathology, University of California, San Francisco, CA 94110

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
3.1. Study subjects
3.2. Enzyme-linked immunoadsorbent assays
3.3. Gelatin zymography
3.4. Western blot analysis
3.5. Immunohistochemistry
3.6. Statistical analysis
4. Results
4.1. Clinical characteristics
4.2. MPO and MMP-9 co-localized in BAVM tissue
4.3. MMP-9 expression correlated with MPO, IL-6, but not with eNOS or CD31
4.4. MMP-9 expression was associated with 125-kDa MMP-9 level
4.5. Assessment of confounding factors on MMP-9 expression
4.6. BAVM tissue displayed higher levels of inflammatory markers
5. Discussion
6. Acknowledgment
7. References

1. ABSTRACT

Brain arteriovenous malformations (BAVM) have high matrix metalloproteinase-9 (MMP-9) expression, the source of which is unclear. We hypothesized MMP-9 production might be due to inflammation in BAVM. Compared to control brain tissues (n=5), BAVM tissue (n=139) had a higher expression (by ELISA) of myeloperoxidase (MPO) (193189 vs. 63, ng/mg, P<.001), MMP-9 (2832 vs. 0.70.6, ng/mg, P<.001), and IL-6 (102218 vs. 0.10.1, pg/mg, P<.001), but not eNOS (11487 vs. 659, pg/mg, P=.09). MMP-9 expression in BAVM highly correlated with myeloperoxidase (R2=.76, P<.001), as well as with IL-6 (R2=.32, P<.001). In contrast, MMP-9 in BAVM poorly correlated with the endothelial marker, eNOS (R2=.03, P=.05), and CD31 (R2 = .004, P= .57). Compared to non-embolized patients (n=46), patients with pre-operative embolization (n=93) had higher levels of myeloperoxidase (236205 vs. 106108, ng/mg, P<.001) and MMP-9 (3335 vs. 1620, ng/mg, P<.001), however the correlation between MMP-9 and myeloperoxidase was equally strong for both groups (R2=.69, n=93, P<.001, for both). MMP-9 expression correlated with the lipocalin-MMP-9 complex, suggesting neutrophils as the MMP-9 source. MPO co-localized with majority of MMP-9 signal by immunohistochemistry. Our data suggest that inflammation is a prominent feature of BAVM lesional phenotype, and neutrophils appear to be a major source of MMP-9 in these lesions.