Extracellular matrix metalloproteinase inducer (CD147) and membrane type 1-matrix metalloproteinase are expressed on tissue macrophages in calcific aortic.

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Extracellular matrix metalloproteinase inducer (CD147) and membrane type 1-matrix metalloproteinase are expressed on tissue macrophages in calcific aortic stenosis and induce transmigration in an artificial valve model Nader Joghetaei, MD, Payam Akhyari, MD, Bernhard H. Rauch, MD, Paul Cullen, MD, Artur Lichtenberg, MD, Martina Rudelius, MD, Jaroslav Pelisek, MD, Roland Schmidt, MD The Journal of Thoracic and Cardiovascular Surgery Volume 142, Issue 1, Pages 191-198 (July 2011) DOI: 10.1016/j.jtcvs.2010.09.051 Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 EMMRIN and MT1-MMP in aortic stenosis. Representative degenerative aortic valve tissue (left) and control aortic leaflet (center) are shown. In arteriosclerotic valves, Elastica van Gieson staining demonstrates a characteristic lesion with dense collagen (staining red), whereas control patients exhibit loose connective tissue with subendothelial localization. There is a clearly visible increase in CD68-positive macrophages and cells demonstrating EMMPRIN and MT1-MMP compared with control leaflets. In arteriosclerotic valves, the majority of cells demonstrate increased protein levels of MMP-2 and MMP-9 when compared with control tissue. Right column demonstrates control stainings (positive controls: breast carcinoma for EMMRIN (1), MT1-MMP (3), MMP-9 (7), and MMP-2 (9), and lymph node for CD68 (5); subclass-matched irrelevant immunoglobulin-G served as negative controls: (2, 4, 6, 8, 10). EMMPRIN-staining cells accumulate in the border zone to calcification (∗) (11), which is stained by alizarin red (12), demonstrating that the changes in EMMPRIN activity occur in the calcific/per-calcific regions of the valve. MTI-MMP, Membrane type 1-matrix metalloproteinase; PGM, phosphoglucomutase. The Journal of Thoracic and Cardiovascular Surgery 2011 142, 191-198DOI: (10.1016/j.jtcvs.2010.09.051) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Double immunofluorescence for EMMPRIN and MT1-MMP in aortic valve tissue. Green fluorescence (fluorescein isothiocyanate) denotes tissue macrophage staining positive for CD68 (A, D), alpha smooth muscle actin (G), and CD31 (J). Red fluorescence (Cy5) demonstrates cells positive for EMMPRIN (B, H, K) and MT1-MMP (E). Double immunofluorescence shows that EMMPRIN and MT1-MMP are co-expressed with CD68 in altered aortic valves (C, F, arrows). This proves that infiltrating macrophages in sclerotic valves express MT1-MMP and EMMPRIN. Blue dye (Hoechst, Invitrogen, Karlsruhe, Germany) identifies nucleated cells. EMMPRIN is not co-expressed with (α-SMA) (I), and EMMPRIN colocalizes with CD31 (L, arrows). Right column represents negative control stainings for EMMPRIN (1), CD68 (2), MT1-MMP (3), α-SMA (4), and CD31 (5). SMA, Smooth muscle actin. The Journal of Thoracic and Cardiovascular Surgery 2011 142, 191-198DOI: (10.1016/j.jtcvs.2010.09.051) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Western blot immunoreactivity of EMMPRIN, MT1-MMP, MMP-2, and MMP-9. Representative Western blot analysis of aortic valve tissue demonstrates increased EMMPRIN (A), MT1-MMP (B), MMP-2 (C), and MMP-9 (D) protein level (to statistically significant extent, P < .05) in aortic stenosis (left column) compared with control aortic valve tissue (right column). ß-actin serves as control protein. MMP, Matrix metalloproteinase. The Journal of Thoracic and Cardiovascular Surgery 2011 142, 191-198DOI: (10.1016/j.jtcvs.2010.09.051) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 A, B, In situ gelatin zymography. Representative zymographs (A) of stenotic aortic valve (upper) demonstrate basic gelatinolytic activity. This activity is dampened by the MMP inhibitor GM6001. In control aortic valves (lower) gelatinolytic activity is weak when compared with stenotic aortic valves. Gelatinolytic specificity of activity is confirmed by incubating samples in the presence of EGTA. Exposure time: 200 ms. Intensity of the in situ zymography fluorescence was quantified using Quantity One software (Version 4.4.1) from BioRad (Hercules, CA). Data are shown (B) as mean ± standard error of the mean of arbitrary fluorescence intensity (n = 4). Basic gelatinolytic activity was significantly increased in stenotic aortic valves (control-diseased) compared with non-diseased aortic valves (control-healthy) (∗P < .05). Moreover, gelatinolytic activity was significantly dampened by the MMP inhibitor GM6001 when compared with the basic gelatinolytic activity of the stenotic aortic valves (#P < .05). OD, Optical density; siRNA, small interfering RNA; MMP, matrix metalloproteinase. The Journal of Thoracic and Cardiovascular Surgery 2011 142, 191-198DOI: (10.1016/j.jtcvs.2010.09.051) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 A, B, Transmigration through an artificial valve surface quantitative analysis (A) and representative images from the transmigration studies (B). Human monocytic MonoMac6 cells were treated with control siRNA or EMMPRIN-silencing siRNA for 48 hours, and their transmigration through the composite of endothelial cell layer and Matrigel (Millipore, Billerica, Mass) was determined. EMMPRIN-silencing siRNA significantly reduced transmigration of monocytic cells compared with pretreatment with control siRNA (∗P < .05). A similar effect was demonstrated by pretreating monocytic cells with the MMP inhibitor GM6001 (Calbiochem, Darmstadt, Germany) compared with control peptide (∗P < .05). EMMPRIN-specific siRNA had no additive effect to MMP inhibition for transmigration of monocytic cells (P = .0621). NS, Not significant; OD, optical density. The Journal of Thoracic and Cardiovascular Surgery 2011 142, 191-198DOI: (10.1016/j.jtcvs.2010.09.051) Copyright © 2011 The American Association for Thoracic Surgery Terms and Conditions