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15575.Full.Pdf Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries Jason L. Johnson*, Sarah J. George, Andrew C. Newby, and Christopher L. Jackson Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, United Kingdom Edited by Jan L. Breslow, The Rockefeller University, New York, NY, and approved September 8, 2005 (received for review July 21, 2005) Matrix metalloproteinases (MMPs) are thought to be involved in tration of a broad-spectrum MMP inhibitor drug failed to exert the growth, destabilization, and eventual rupture of atheroscle- any beneficial effect on atherosclerosis measured in the aortas of rotic lesions. Using the mouse brachiocephalic artery model of low-density lipoprotein receptor knockout mice (8). Contradic- plaque instability, we compared apolipoprotein E (apoE)͞MMP-3, tory results have also been obtained in studies of MMP trans- apoE͞MMP-7, apoE͞MMP-9, and apoE͞MMP-12 double knockouts genic and knockout mice (7, 9–11). However, none of these with their age-, strain-, and sex-matched apoE single knockout studies directly addressed the issue of plaque instability. controls. Brachiocephalic artery plaques were significantly larger in We have recently described a model of plaque instability in which apoE͞MMP-3 and apoE͞MMP-9 double knockouts than in controls. spontaneous plaque ruptures and rupture-related events are ob- The number of buried fibrous layers was also significantly higher served at an early time point in the proximal part of the brachio- in the double knockouts, and both knockouts exhibited cellular cephalic arteries of fat-fed apoE knockout mice (12). Acute plaque compositional changes indicative of an unstable plaque pheno- disruption and fibrin deposition correlate closely with the presence type. Conversely, lesion size and buried fibrous layers were re- of buried fibrous layers (akin to human healed plaque ruptures) in duced in apoE͞MMP-12 double knockouts compared with controls, lesions from mice at this time point. Therefore, buried fibrous layers and double knockouts had increased smooth muscle cell and can be used as a surrogate marker of previous plaque disruption͞ reduced macrophage content in the plaque, indicative of a stable instability, and we are able to compare the effects of several MMP plaque phenotype. ApoE͞MMP-7 double knockout plaques con- gene deletions in the same defined anatomical location. We inves- tained significantly more smooth muscle cells than controls, but tigated the contributions of four members of the MMP family that neither lesion size nor features of stability were altered in these have been suggested to play a role in atherosclerotic plaque animals. Hence, MMP-3 and MMP-9 appear normally to play pro- instability: MMP-3 (stromelysin-1), MMP-7 (matrilysin-1), MMP-9 tective roles, limiting plaque growth and promoting a stable (gelatinase B), and MMP-12 (macrophage metalloelastase). We plaque phenotype. MMP-12 supports lesion expansion and desta- determined their effects on progression and atherosclerotic lesion bilization. MMP-7 has no effect on plaque growth or stability, phenotype in the brachiocephalic arteries of apoE knockout mice. although it is associated with reduced smooth muscle cell content in plaques. These data demonstrate that MMPs are directly in- Methods volved in atherosclerotic plaque destabilization and clearly show Animals. MMP-3Ϫ/Ϫ (background strain B10.RIII), MMP-7Ϫ/Ϫ that members of the MMP family have widely differing effects on (background strain C57BL͞6), MMP-9Ϫ/Ϫ (background strain atherogenesis. CD1), and MMP-12Ϫ/Ϫ (background strain 129) mice were kindly provided by J. Mudgett (Merck Research Laboratories, Rahway, animal models ͉ atherosclerosis NJ) and S. Shapiro (Harvard Medical School, Boston). ApoEϪ/Ϫ mice were kindly provided by J. Breslow (The Rockefeller Univer- Ϫ Ϫ atrix metalloproteinases (MMPs) are a group of Ͼ20 zinc- sity, New York). The strain background of the apoE / animals was Mcontaining endopeptidases that are either secreted or ex- 71% C57BL͞6, 29% 129, as determined by fingerprinting of tail-tip Ϫ Ϫ pressed at the cell surface of all of the main vascular cell types. DNA. ApoE / mice were crossed with MMP knockouts to Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ MMPs have overlapping specificities, but each can process at least generate apoE / ͞MMP-3 / , apoE / ͞MMP-7 / , apoE / ͞ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ one extracellular matrix component, and many nonmatrix sub- MMP-9 / , and apoE / ͞MMP-12 / double knockout mice as Ϫ Ϫ strates have also been described. Given this complexity it is not well as their relevant age-, strain-, and sex-matched apoE / single surprising that multiple roles for MMPs have been proposed, knockout littermate controls. Genomic DNA was extracted from including regulation of cell migration, proliferation, and death. As tail tips for genotyping by PCR. The housing and care of the animals a result, roles for MMPs in atherosclerotic plaque growth and and all of the procedures used in these studies were performed in MEDICAL SCIENCES fibrous cap formation have been suggested (1). On the other hand, accordance with the guidelines and regulations of the University of the presence of elevated mRNA, protein, and activity levels of Bristol and the United Kingdom Home Office. MMPs within atherosclerotic lesions, particularly at the shoulder regions of the fibrous cap (2–5), has led to the suggestion that they Experimental Design. As demonstrated (12), atherosclerotic lesions degrade strength-giving extracellular matrix components, including develop more rapidly in the brachiocephalic arteries of male mice fibrillar collagens. By this mechanism MMPs could promote ath- compared with females; therefore only male animals were used in erosclerotic plaque destabilization, the main cause of myocardial these studies. To evaluate any effect of MMP gene knockout on infarction in humans. normal development of the brachiocephalic artery, subsets of Intervention studies in animal models have been used to animals were fed standard chow diet from weaning for 6 weeks and investigate the potential roles of MMPs in cardiovascular dis- then terminated. To evaluate atherosclerosis, animals of 8 weeks of ease. For example, inhibition of MMP activity by adenovirus- mediated delivery of the gene for human tissue inhibitor of metalloproteinases (TIMP)-1 reduced lesion size in the aortic This paper was submitted directly (Track II) to the PNAS office. root of apolipoprotein E (apoE) knockout mice (6). However, Abbreviations: MMP, matrix metalloproteinase; apoE, apolipoprotein E. atherosclerotic lesion size and stability were unaffected in the *To whom correspondence should be addressed. E-mail: [email protected]. aortas of mice deficient for TIMP-1 (7). Additionally, adminis- © 2005 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0506201102 PNAS ͉ October 25, 2005 ͉ vol. 102 ͉ no. 43 ͉ 15575–15580 Downloaded by guest on September 26, 2021 Table 1. Brachiocephalic artery morphometry in chow-fed apoE͞MMP double knockout mice Lumen area, Media area, Total vessel area, Internal elastic lumina Study group ϫ103 ␮m2 ϫ103 ␮m2 ϫ103 ␮m2 length, ␮m ApoEϪ͞Ϫ͞MMP-3ϩ͞ϩ (n ϭ 6) 149 Ϯ 15 70 Ϯ 3 218 Ϯ 17 1,364 Ϯ 69 ApoEϪ͞Ϫ͞MMP-3Ϫ͞Ϫ (n ϭ 6) 147 Ϯ 13 67 Ϯ 7 214 Ϯ 20 1,358 Ϯ 59 ApoEϪ͞Ϫ͞MMP-7ϩ͞ϩ (n ϭ 6) 185 Ϯ 12 60 Ϯ 4 245 Ϯ 14 1,521 Ϯ 51 ApoEϪ͞Ϫ͞MMP-7Ϫ͞Ϫ (n ϭ 6) 196 Ϯ 13 57 Ϯ 8 254 Ϯ 19 1,568 Ϯ 52 ApoEϪ͞Ϫ͞MMP-9ϩ͞ϩ (n ϭ 6) 156 Ϯ 11 59 Ϯ 5 239 Ϯ 25 1,481 Ϯ 85 ApoEϪ͞Ϫ͞MMP-9Ϫ͞Ϫ (n ϭ 6) 179 Ϯ 21 59 Ϯ 7 215 Ϯ 18 1,396 Ϯ 85 ApoEϪ͞Ϫ͞MMP-12ϩ͞ϩ (n ϭ 6) 168 Ϯ 948Ϯ 4 202 Ϯ 13 1,385 Ϯ 52 ApoEϪ͞Ϫ͞MMP-12Ϫ͞Ϫ (n ϭ 6) 153 Ϯ 12 57 Ϯ 3 225 Ϯ 10 1,449 Ϯ 39 Double knockout mice and single knockout controls were fed chow diet and terminated at 6 weeks of age, and the brachiocephalic artery was removed. Vessel compartment areas were determined by computerized morphometry. There were no significant differences between double knockout and single knockout control mice. Values represent mean Ϯ SEM. age were fed high-fat diet containing 21% (wt͞wt) pork lard and 1:200 in 1% (wt͞vol) BSA in PBS, and then horseradish peroxidase- supplemented with 0.15% (wt͞wt) cholesterol (Special Diet Ser- labeled Extravidin [diluted 1:400 in 1% (wt͞vol) BSA in PBS]. vices, Witham, U.K.) for 8 weeks. To ensure that the studies were Color was developed with 0.05% (wt͞vol) 3,3Ј-diaminobenzidine, adequately powered, group sizes in excess of 20 animals were used. and then the nuclei were counterstained with Mayer’s hematoxylin. Positive cells were counted and expressed as a percentage of the Plasma Lipid Profile. Heparinized plasma samples were collected total number of nucleated cells. A negative control, where the at termination, and plasma lipid profiles were determined as primary antibody was replaced with either mouse or rat IgG at described (12). the same dilution, was always included. Termination. Animals were anaesthetized by i.p. injection of sodium Morphological Analysis. Sections were inspected for the presence of pentobarbitone before exsanguination by arterial perfusion via the buried fibrous layers, smooth muscle cell-rich layers, invested with abdominal aorta with PBS at a constant pressure of 100 mmHg (1 ϭ elastin, and usually overlain with foam cells, within the body of the mmHg 133 Pa), with outflow through the incised jugular veins. plaque. These represent previous healed plaque ruptures (12) and This process was followed by constant pressure perfusion with were also counted. zinc-HCl fixative [0.05% (wt͞vol) calcium acetate, 0.5% (wt͞vol) zinc acetate, 0.5% (wt͞vol) zinc chloride, 0.1 mol͞liter Tris⅐HCl, pH Statistical Analysis. Values are expressed as mean Ϯ SEM. For the 7.4]. The brachiocephalic artery was removed from each animal.
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