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J Thorac Cardiovasc Surg 2007;133:1028-1036
© 2007 The American Association for Thoracic Surgery
Surgery for Acquired Cardiovascular Disease |
a Department of Cardiothoracic Surgical Research, Division of Cardiothoracic Surgery, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
b Division of Cardiothoracic Surgery, University of Pennsylvania, Philadelphia, Penn.
Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.
Received for publication April 27, 2006; revisions received September 27, 2006; accepted for publication October 9, 2006. * Address for reprints: John S. Ikonomidis, MD, PhD, Associate Professor of Surgery, Division of Cardiothoracic Surgery, Medical University of South Carolina, Suite 409 CSB, 96 Jonathan Lucas Street, Charleston, SC 29425. (Email: ikonomij{at}musc.edu).
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Abstract |
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Methods: Ascending thoracic aortic aneurysm samples taken from patients with bicuspid aortic valve (n = 53) and patients with tricuspid aortic valve (n = 46) were assessed for representative subtypes of all matrix metalloproteinase classes and all 4 known tissue inhibitors of metalloproteinases. Levels were compared [optical density units, median (interquartile range)] both to reference control ascending aortic samples (n = 26) and within each valve group by aneurysm diameter (
3.9 cm, 4.0-5.9 cm and 
6.0 cm).
Results: Different and specific matrix metalloproteinase and tissue inhibitors of metalloproteinase profiles were observed in the ascending thoracic aortic aneurysm groups. In bicuspid aortic valves, matrix metalloproteinase-2 increased by 34% when compared with either tricuspid aortic valves or control (P < .05), and matrix metalloproteinase-14 decreased by 59% compared with tricuspid aortic valves (P < .05). In tricuspid aortic valve samples, tissue inhibitors of metalloproteinase-2 decreased by 35% when compared with either tricuspid aortic valves or control (P < .05), and matrix metalloproteinase-13 increased by 140% in the 4.0- to 5.9-cm diameter range (P < .05).
Conclusions: A unique matrix metalloproteinase and tissue inhibitor of metalloproteinase portfolio was observed in ascending thoracic aortic aneurysms from patients with bicuspid aortic valve compared with patients with tricuspid aortic valve. These differences, suggesting disparate mechanisms of extracellular matrix remodeling, may provide unique biochemical targets for ascending thoracic aortic aneurysm prognostication and treatment in these 2 groups of patients.
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Introduction |
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These include nonspecific medial degenerative disease associated with tricuspid aortic valves (TAVs) and ATAAs associated with congenital bicuspid aortic valves (BAVs).1-4 Recent work has shown that differences between these 2 ATAA populations exist at both the molecular and histologic level but that these differences remain incompletely characterized.1-4 A central theme with regard to ATAA formation is disturbances in proteolytic activity within the aneurysm wall.5-7 The matrix metalloproteinases (MMPs) constitute a large family of enzymes that process or degrade the extracellular matrix. The MMPs are grouped into classes based on their primary substrate specificities. An association has been established between increases in MMPs and development of aortic aneurysms.5,6 Primary endogenous control of MMP activity is maintained through 4 tissue inhibitors of metalloproteinases (TIMPs).7 In aortic aneurysms, imbalances in the ambient MMP and TIMP profiles within the aortic wall are observed that favor net proteolysis.6 The possible contribution of changes in MMP and TIMP profiles within the aortic wall of ATAAs from patients with BAV has been incompletely quantified. Further, whether and to what degree these profiles differ from ATAAs from patients with TAV is unknown. Accordingly, the present study tested the hypothesis that specific differences exist with respect to the MMP and TIMP cassettes expressed in ATAAs in patients with BAV versus patients with TAV.
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Materials and Methods |
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2). The ages within the groups were as follows: median (interquartile range): control, 52 (18) years; BAV, 60 (14) years; TAV, 72 (15) years (P < .05 BAV/TAV from control, TAV from BAV). The aortic diameters [median (interquartile range)] were not different between ATAA groups but different from control: control, 2.8 (0.3) cm; BAV, 5.1 (0.7) cm; TAV, 5.5 (1.6) cm (P < .05 BAV/TAV from control). The study was approved by the Institutional Review Boards of both The Medical University of South Carolina and The University of Pennsylvania. Informed consent was obtained from all patients.
Immunoblotting and Zymography
Aortic sample preparations
The resected specimens were placed in tubes and snap-frozen in a dry ice/methanol slurry prior to storage at –80°C. For analysis, the samples were homogenized in a cold acidic extraction buffer solution to prevent proteolytic activation during the extraction process.8 The homogenate was then centrifuged (4°C, 10 minutes, 1200g), the supernatant concentrated (Centriplus; Millipore, Bedford, Mass), and the final protein concentration of the aortic extracts was determined (BCA Protein Assay; Pierce, Rockford, Ill).
Zymography
Relative aortic MMP gelatinase activity was examined by substrate-specific zymographic analysis as described previously.9 The aortic extracts (10 µg total protein) were loaded onto electrophoretic gels (sodium dodecylsulfate–polyacrylimide gel electrophoresis) containing 1 mg/mL of gelatin followed by washing and incubation in an MMP substrate buffer for 12 hours at 37°C. After incubation, the gels were stained using 0.1% Coomassie blue and destained in water. An MMP-2/-9 recombinant standard (CC073, Chemicon, Temecula, Calif) was added to each gel to serve as a positive control.
Immunoblotting
The relative abundances of MMPs/TIMPs were examined by using quantitative immunoblotting techniques.8,9 Briefly, 10 µg of aortic extract was loaded onto a 4% to 12% Bis-Tris gradient gel (Invitrogen Corp, Carlsbad, Calif) and subjected to electrophoresis. The fractionated proteins were transferred to nitrocellulose membranes (0.45 µm, Bio-Rad, Hercules, Calif) and subsequently blocked with 5% nonfat dry milk in phosphate-buffered saline solution (PBS) for 1 hour at room temperature. The membranes were incubated in diluted antiserum (0.4 µg/mL in 5% nonfat dry milk/PBS) containing specific antibodies representative of all nongelatinase MMP classes (collagenases, elastases, stromelysins, matrilysins, and the membrane-type MMPs) and all known TIMPs (see Appendix). Following incubation with the primary antibody, the membranes were extensively washed (3 x 10 minutes, 25 mL PBS), and a secondary peroxidase-conjugated antibody (species-dependent on primary antibody used) was applied (1:5000, 5% nonfat dry milk/PBS) and incubated for 1 hour at room temperature. Following washing (4 x 15 minutes, 25 mL PBS), immunoreactive signals were detected by briefly incubating the membranes with a chemiluminescent substrate (Western Lightning Chemiluminescence Reagent Plus, Perkin Elmer, Piscataway, NJ) and exposing the blot to film (Hyperfilm, GE Healthcare, Piscataway, NJ).
Data Analysis
The zymograms and immunoblot films were digitized and quantitative image analysis (Gel Pro Analyzer; Media Cybernetics, Silver Spring, Md) was performed.
All statistical procedures were performed using the Stata statistical software package (Stata Corporation, College Station, Tex). The analysis was conducted in 2 parts. For the first analysis, all samples in the BAV and TAV groups with an ascending size less than 4.0 cm were excluded. The MMP and TIMP data distributions for the reference controls, BAV group, and TAV group were tested for normality using the Shapiro–Wilk test. The results indicated nonparametricity, and hence a two-sample Mann–Whitney rank sum test was performed to test comparisons between groups.
For the second portion of the analysis, the raw data was categorized by ascending aortic size: 3.9 cm, 4.0-5.9 cm, and 6.0 cm. The 3.9-cm group was composed of all aortic samples with diameters 3.9 cm across the 3 groups (26 reference controls, 3 BAVs, and 9 TAVs; n = 38). Spearman’s rank correlation coefficient testing was used to determine correlation between ascending aortic size as categorized and MMPs/TIMPs. Comparisons within the BAV and TAV groups were performed using a two-sample Mann–Whitney rank sum test.
Regression analyses were also performed testing for the effects of age, hypertension, aortic valve pathology (stenosis versus regurgitation), and aortic diameter indexed to body surface area.10
Data were calculated as a percentage of the reference control group set to a mean of 100% and expressed as the median (interquartile range). As such, in the succeeding figures, the control values will deviate from 100 due to expression of the median, not the mean, value.
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Results |
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Size Analysis: BAV
In the BAV group, Spearman’s testing revealed weak but significant correlations between MMP-2 (Figure 2, rho value 0.243, P = .02) and MMP-14 (Figure 3, rho value –0.313, P = .003) and aneurysm size.
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3.9-cm group. TIMP-1 was decreased in the 6.0-cm size range relative to the 3.9-cm group.
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3.9-cm group followed by a reduction in the 6.0-cm size range. In addition, decreased MMP-1, MMP-3, and TIMP-2 were demonstrated in the 4.0- to 5.9-cm diameter size range compared with the 3.9-cm group. MMP-7 was seen to be increased (Figure 4) in the in the 6.0-cm size range compared with the 3.9-cm group.
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Discussion |
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Congenital BAVs are prone to development of both stenosis and regurgitation and are associated with aortic pathology such as coarctation and dissection, in addition to an increased incidence of ATAAs.11 Current hypotheses with regard to BAV-related ATAA formation include genetic abnormalities in the neural crest-origin cells in the ascending aorta and the flow hypothesis, in which turbulent blood flow across the BAV results in hemodynamic stress on the ascending aortic wall, especially the right anterolateral (outer) convexity.11,12 Although the histopathologic description of the manifestations of BAV with respect to ATAAs is improving,12 the underlying biochemical basis for these structural changes within the extracellular matrix remains poorly understood. It is now recognized that alterations in a specific extracellular matrix proteolytic cascade involving the MMPs and TIMPs occur in various cardiovascular disease states such as abdominal aortic aneurysms as well as ATAAs.5,6 However, a comparative, comprehensive quantitation of MMPs and TIMPs that occur within ATAAs in BAV with respect to TAV has not been performed. Accordingly, the present study measured representative MMPs from each of the major classes of this metalloprotease family, as well as all of the currently known TIMPs in a sample of ATAAs resected from patients with BAV and TAV. When compared with reference control patients, the unique findings from this study were that specific MMP and TIMP profiles emerged in the ATAAs from patients with BAV compared with the patients with TAV. For example, significantly increased MMP-2 and decreased membrane type-1 MMP (MMP-14) occurred in the ATAAs from patients with patients with BAV. In contrast, the TAV aortic samples showed increased MMP-13 and decreased TIMP-2. These findings, with respect to processing of extracellular matrix constituents as well as other biologic signaling molecules, would suggest that a unique proteolytic process occurs in the development of ATAAs in patients with BAV, which may hold future diagnostic and prognostic implications.
Several studies to date have compared MMP and TIMP expression in BAV versus TAV aortic samples.1-4 Fedak and colleagues1 reported increased MMP-2 in BAV aortic samples compared with TAV samples with no changes in MMP-9 between the 2 groups. Boyum and colleagues2 demonstrated both increased MMP-2 and MMP-9 in BAV samples, with no differences in TIMP-1 and TIMP-2 relative to TAV aortic tissue. Koullias and associates3 examined valve tissue from patients with BAV and TAV, of which half of the population required a concomitant aortic procedure. The results showed increased MMP-2 and MMP-9 in the BAV tissue with nonsignificant trends toward increased TIMP-1 and TIMP-2 compared with the patients with TAV. Lemaire and coworkers4 compared ATAA tissue from patients with BAV and patients with TAV to control ascending aortic samples and found increased MMP-2 in the BAV samples compared with TAV and control and increased MMP-9 in the TAV samples compared with BAV and control, with no differences in TIMP-1 and TIMP-2. The results mentioned earlier raise several points. First, of the greater than 25 known MMPs and 4 TIMPs,13 the studies mentioned earlier provide a limited profile of MMP and TIMP types in BAV and TAV tissue. The present study contributes to the data described earlier by providing a more comprehensive survey of the known MMP classes in addition to all 4 TIMPs. Second, there is disparity with regard to the involvement of MMP-9 in the pathogenesis of these common forms of ATAA, in contrast to abdominal aortic aneurysms where MMP-9 is considered to be very important.5,6 The present study showed little change in MMP-9 in either BAV or TAV tissue. Third, each study discussed earlier showed an increase in MMP-2 in the BAV group, which is also supported by the findings of the present study. Finally, in contrast to the previous studies, the larger sample size of this study allowed comparison of numerous MMPs and TIMPs by increasing aneurysm size.
MMPs
For BAV samples, the significant findings of this study were increased MMP-2 and decreased MMP-14 overall, with these results seen particularly in the 4.0- to 5.9-cm size range. MMP-2, or gelatinase A, is synthesized by resident cells in the aortic wall such as fibroblasts, smooth muscle cells, and endothelial cells.13 It is not released by inflammatory cells such as neutrophils and macrophages, and recent work has demonstrated a reduced inflammatory infiltrate seen in BAV-associated ATAAs compared with TAV-associated ATAAs, consistent with these observations.4 MMP-2, in addition to its elastolytic properties, also cleaves numerous collagen subtypes (I-V, XI), laminin, and fibrillin-1.14,15 It has recently been shown that extracellular matrix remodeling and dilatation of the ascending aorta in patients with BAV occurs in an asymmetrical fashion, which is most pronounced in the right anterolateral aspect (convexity).12 The study by Della Corte and colleagues12 demonstrated a reduction in collagens I and III in addition to laminin in the outer convexity compared with the inner concavity of BAV-associated ATAAs, consistent with MMP-2 activity. Further, Fedak and associates1 showed decreased fibrillin-1 in BAV-associated ATAA tissue consistent with the finding of increased MMP-2 observed in this population. In addition, it is well described that MMP-2 is activated in response to turbulent flow and shear stresses such as those seen across a BAV and disproportionally in the outer curvature of the ascending aorta.16 However, the present study showed no statistical correlation between valve pathology and aneurysm formation in either valve group, suggesting that the turbulent flow relationship may be 1 of many factors acting in concert to form aneurysms.
With regard to MMP-2 activation, it is interesting that MMP-14 is decreased in the setting of an increase of MMP-2 in this population. One major function of MMP-14 is the activation of MMP-2 by a mechanism involving TIMP-2.17,18 Although not quantified, the immunoblotting results (Figure 1) showed an increase in the active form (66 kd) of MMP-2 in BAV-associated ATAA tissue, suggesting increased MMP-2 activity. When taken together with the observed decrease in MMP-14, this suggests that an alternative mechanism of MMP-2 activation is operational, a finding that warrants further investigation.
For the TAV samples, perhaps the most significant finding is that of increased MMP-13 in the 4.0- to 5.9-cm size range, with a decrease in this species with larger aneurysm size. MMP-13, or collagenase-3, is a powerful proteinase produced by native cells in the aortic wall, and its expression is strictly controlled under normal physiologic conditions. It has a broad substrate specificity including many collagen types (I-IV, IX, X, XIV), tenascin C, fibronectin, aggrecan, versican, and osteonectin.18 In addition, MMP-13 can inactivate chemokines, such as monocyte chemoattractant protein-3 and stromal cell-derived factor-1.19 MMP-13 also appears to be involved in the activation of pro-transforming growth factor-ß3. MMP-13 expression is also detected in pathologic conditions that are characterized by the destruction of normal collagen-containing tissue architecture, including abdominal aortic aneurysms.20 The unique finding of increased MMP-13 in the TAV group in this study is consistent with extracellular matrix destruction and perhaps an active expansion phase in medium-sized ATAAs. As the aneurysm grows further, there may be a sufficient decline of resident cells (by senescence and apoptosis) to decrease the amount of MMP-13 produced, explaining the decline in MMP-13 demonstrated for larger aneurysm sizes. In addition, regression analysis showed a positive correlation between MMP-13 and age. Previous work has shown that tissue MMP levels are age sensitive,13,14 and the associative result shown in the present study suggests that MMP-13 may be even more important for aneurysm formation in older patients.
Another interesting finding with the TAV group is the demonstration of increased MMP-7 in large aneurysms. MMP-7, or matrilysin, is a small-molecular-weight MMP elaborated by many cell types, both constitutive and inflammatory. It serves numerous functions including extracellular matrix degradation (elastin, type IV collagen, fibronectin, vitronectin, aggregan, and proteoglycans), MMP (–1, –2, –9) activation, and regulation of bioactive molecules controlling inflammation, cell proliferation, apoptosis, invasion, and angiogenesis.21 Of potential relevance to the present study is the ability of MMP-7 to cleave tumor necrosis factor (TNF)-
precursor to release soluble TNF-, which, through binding to TNF-receptor 1, may increase apoptosis. In abdominal aortic aneurysms, increased MMP-7 levels have been demonstrated only in the aneurysm wall and not luminal thrombus, suggesting that MMP-7 was elaborated more likely by resident cells within the aortic wall than by inflammatory cells.22,23 As such, MMP-7 may play an important late role on aneurysm progression though promotion of continued cellular attrition within the aortic wall.
In general, the derangements described earlier occurred for MMPs that are constitutively expressed by cells resident within the aortic wall (fibroblasts, smooth muscle cells). There appears, at least from this analysis, to be less of a proteolytic contribution from those MMPs elaborated from inflammatory cells (eg, MMP-8, MMP-9, MMP-12) for the ascending aorta than that seen in the abdominal aorta.5,24,25 It is possible that in response to pathologic stimuli, the resident cells undergo a pathologic transformation, resulting in increased MMP synthesis and release with increasing aneurysm size. Additional studies are required to address this hypothesis.
TIMPs
Primary endogenous control of MMP activity is maintained through 4 TIMPs. Each member of the TIMP family exhibits a distinct pattern of affinity for particular MMPs through a reversible, 1:1 interaction,7 and stoichiometry shifts between MMPs and TIMPs have been shown to favor abdominal aortic aneurysm formation.6,12 In addition, TIMPs have a number of other effects including activation of other MMPs, potentiation of growth factors, and instigation or suppression of apoptosis.7 In the present study, a complete survey of all 4 TIMPs was undertaken including TIMP-1, highly expressed in the aorta,6,12 and the cardiovascular system–specific TIMP-4.26 In the present study, TIMP-1 was decreased in the BAV group in the 6.0-cm size range and TIMP-2 was decreased in the TAV group in the 4.0- to 5.9-cm size range. Decreased TIMPs in the setting of increased MMPs as shown earlier could represent a stoichiometry shift of proteolytic activity versus endogenous inhibition favoring extracellular matrix breakdown and ATAA growth.
Clinical Significance
The present study identified specific and different MMP and TIMP species produced in tissue of BAV- versus TAV-associated ATAAs. These species may provide important therapeutic targets in that tailored inhibitory strategies aimed at these MMPs may decrease or halt ATAA formation while minimizing the untoward side effect profiles typically associated with global MMP inhibition. Also, novel imaging or blood-testing techniques may be developed in which specific MMP imaging within the aorta may be used for diagnostic and prognostic assessment. For example, in the TAV group, imaging or plasma testing showing increased MMP-13 could indicate a medium-sized ATAA in a growth phase, and the later emergence of MMP-7 could then indicate a more mature, larger-sized ATAA with a different expansion rate.
Because this study was performed on resected aortic specimens at the time of surgery, inherent limitations exist. First, it is unclear whether the MMP and TIMP profiles measured are reflective of a specific stage in aneurysm progression or represent a summary of multiple phases. As stated earlier, further studies are required to develop other techniques of aneurysm characterization such as specific MMP plasma assays or imaging modalities to more carefully address this limitation. In addition, the potential for regional aortic heterogeneity implies that MMP and TIMP profiles seen in the ascending aorta may be different from the aortic arch or descending thoracic aorta and hence are not translatable. Also important is that caution must be exercised in extrapolating these MMP measurement results to true matrix-degrading activity and thus a more direct assessment of activity is required. By strict measurement criteria, some of the samples obtained were not from aortas that would truly be considered to be aneurysmal. However, assessment of these patients is also important because this represents the early stages of aneurysm formation where an early intervention may reduce, arrest, or reverse the dilatation process. Although different MMP cassettes were demonstrated for BAV- and TAV-associated ATAA tissue, a true cause-effect relationship between these changes and aneurysm expansion was not demonstrated and thus further studies are warranted. Comparison of aneurysmal aorta to adjacent nondilated aorta could be helpful in this regard. Finally, careful examination of the inner and outer curvature of the aneurysm wall is required to define regional MMP and TIMP profiles as they relate to disparities in extracellular matrix remodeling within the aneurysm.
Nevertheless, the results from the present study imply that a unique and differential extracellular matrix proteolytic signature exists in within the aorta of patients with BAV as opposed to patients with TAV with ascending aortic aneurysm disease and suggests that these disease processes do not follow a common etiology.
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Appendix |
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Footnotes |
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References |
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J. A. Phillippi, E. A. Klyachko, J. P. Kenny IV, M. A. Eskay, R. C. Gorman, and T. G. Gleason Basal and Oxidative Stress-Induced Expression of Metallothionein Is Decreased in Ascending Aortic Aneurysms of Bicuspid Aortic Valve Patients Circulation, May 12, 2009; 119(18): 2498 - 2506. [Abstract] [Full Text] [PDF]
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T. M. Tadros, M. D. Klein, and O. M. Shapira Ascending Aortic Dilatation Associated With Bicuspid Aortic Valve: Pathophysiology, Molecular Biology, and Clinical Implications Circulation, February 17, 2009; 119(6): 880 - 890. [Full Text] [PDF]
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 A. Ali, Y. Abu-Omar, A. Patel, Z. Ali, A. Y. Sheikh, A. Akhtar, A. Pavlovic, P. Theodorou, T. Athanasiou, and J. Pepper Valve failure following homograft aortic valve replacement: does implantation technique have an effect? Eur. Heart J., June 1, 2008; 29(11): 1454 - 1462. [Abstract] [Full Text] [PDF]
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A. Della Corte, C. Quarto, C. Bancone, C. Castaldo, F. Di Meglio, D. Nurzynska, L. S. De Santo, M. De Feo, M. Scardone, S. Montagnani, et al. Spatiotemporal patterns of smooth muscle cell changes in ascending aortic dilatation with bicuspid and tricuspid aortic valve stenosis: Focus on cell matrix signaling J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 8 - 18. [Abstract] [Full Text] [PDF]
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