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J Thorac Cardiovasc Surg 2008;135:8-18
© 2008 The American Association for Thoracic Surgery
Surgery for Acquired Cardiovascular Disease |
a Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy
b Department of Biomorphological and Functional Sciences, "Federico II" University, Secondo Policlinico, Naples, Italy.
Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-9, 2007.
Received for publication May 1, 2007; revisions received August 23, 2007; accepted for publication September 20, 2007. * Address for reprints: Alessandro Della Corte, MD, Via P. Neruda, 6, 81031 Aversa CE, Italy. (Email: aledellacorte{at}libero.it).
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Abstract |
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Methods: Wall specimens were retrieved from both the greater and the lesser curvature ("convexity" and "concavity") of 14 nonaneurysmal and 12 aneurysmal aortas (aortic ratios 1.2 and 1.5, respectively) and from 3 heart donors (normal). Immunochemistry was performed for detection of apoptotic (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling [TUNEL]-positive) and proliferating (Ki-67-positive) smooth muscle cells and for semiquantification of matrix proteins (collagens, fibronectin, tenascin, laminin). Co-immunoprecipitation assessed the extent of Bcl-2-modifying factor binding to Bcl-2, indicating a matrix-derived cytoskeleton-mediated proapoptotic signaling. Polymerase chain reaction allowed for quantification of messenger RNA expression for Bcl-2.
Results: In both bicuspid and tricuspid aneurysms, fibrillar collagens were reduced, whereas fibronectin and tenascin were increased compared with those in normal conditions. These matrix alterations were already evident in bicuspid nonaneurysmal aortas at the convexity, with significant elevation of apoptotic indexes (P = .02 bicuspid vs normal; P = .48 tricuspid vs normal). Apoptotic indexes correlated with aortic dimensions only in tricuspid aortas (P = .01). No significant increase in Ki-67 was found. Higher levels of Bcl-2-modifying factor-Bcl-2 binding were found in bicuspid nonaneurysmal aorta versus tricuspid (P = .03) and normal aortas (P = .01). Bcl-2 messenger RNA expression was reduced in the bicuspid aorta versus normal (P = .08).
Conclusions: Smooth muscle cell apoptosis with bicuspid aortic valve stenosis occurred before overt aortic dilation, mainly at the convexity, where wall stress is expectedly higher. In this setting, a matrix-dependent proapoptotic signaling was evidenced by increased Bcl-2-modifying factor-Bcl-2 binding. Stress-dependent bicuspid aortic valve matrix changes may trigger early apoptosis by inducing cytoskeletal rearrangement.
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and extracellular matrix (ECM) rearrangement.3,4 Recently, remarkable improvements have been achieved in the knowledge of the mechanisms underlying ascending aortic dilations,1-4 but without identifying definite pathogenetic sequences. Indeed, medial degeneration can underlie a variety of anatomoclinical conditions (eg, the senile aorta, poststenotic dilations, idiopathic or syndromic aneurysms, dissections), suggesting different possible mechanisms of lesion development.1 In particular, aortic dilations associated with congenital bicuspid aortic valve (BAV) are known to differ from those with tricuspid aortic valve (TAV) disease in terms of histopathology,2 anatomic configuration,5 and natural history.6
In our preliminary investigation, we4 defined medial ECM changes in BAV-associated dilations, observing a decrease in collagen content versus normal aorta and an increase in fibronectin and the expression of tenascin. However, no comparison with TAV-associated dilations and no distinction between early changes and mature lesions were performed. The present study was undertaken as a more in-depth continuation of the previous one,4 with the aim to assess spatial and temporal patterns of ECM protein and SMC changes in BAV- and TAV-associated aortic dilations. Moreover, inasmuch as changes in the ECM composition, including those previously observed in BAV aortopathy,3,4 are known to possibly influence SMC phenotype, proliferation, survival, and synthetic activity,7,8 we focused on the hypothesis that SMC apoptosis in ascending dilations could be provoked by matrix-derived signaling. Anoikis (the ancient Greek word for homelessness) is the term indicating apoptosis caused by the loss of normal adhesion of cells to a normally organized ECM, occurring via altered cell "tensegrity," the tensional integrity of the cytoskeleton.9 Matrix disarray and/or cell detachment can induce loss of cytoskeletal integrity, cell shape changes, and eventually cell death9,10: thus, "amorphosis" is considered as a typical feature/modality of anoikis.10,11 Proapoptotic cues are known to be transmitted to cells by the ECM in both the settings of vascular physiology and disease.9 In the present study, we hypothesized that matrix-derived proapoptotic signals could be involved in the development of BAV aortopathy.
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soon after the aortotomy was performed, we retrieved 2 full-thickness aortic wall samples distal to the sinotubular junction (maximal dilation level) in each patient: one at the convexity and the other at the concavity (from the two ends of the transverse aortotomy in patients without indication to concomitant ascending aorta replacement). Wall specimens were retrieved at the same levels also from 3 normotensive heart donors during multiorgan procurement (2 men, 1 woman; mean age 40 ± 3 years; mean diameter 3.4 ± 0.15 cm). Thus, 58 specimens overall were available for examination. The study was approved by our institution’s ethical committee and patients gave informed consent.
Immunohistochemistry of Matrix Proteins
Specimens (n = 52) were fixed in buffered 10% formalin, embedded in paraffin, and sectioned. Serial 4 µm-thick sections of aortic specimens were deparaffinized, covered with primary monoclonal antibodies against type I collagen, tenascin-C, and laminin or polyclonal antibody for fibronectin (Sigma-Aldrich, St Louis, Mo), and type III collagen (Santa Cruz Biotechnology Inc., Santa Cruz, Calif), and incubated in a moist chamber for 1 hour at 37°C. After washings in phosphate-buffered saline (PBS), they were covered with fluoresceinated secondary antibodies (Sigma-Aldrich) and reincubated. Nuclei were stained with propidium iodide, and then sections were mounted in Vectashield mounting medium (Vector Laboratories, Burlingame, Calif) and observed with Leica DMLB fluorescence microscope (Leica Microsystems, Inc, Bannockburn, Ill). Moreover, a Zeiss LSM-510 confocal microscope (Karl Zeiss International, Jena, Germany) was used to obtain full-thickness reconstructions of the aortic wall to describe spatial distribution of proteins. To obviate the possible interference of elastin autofluorescence, however, quenched by pretreatment with toluidine blue 0.1% solution, we also performed the immunoperoxidase method for countercheck, using the standard avidin-biotin-peroxidase complex technique and the L.V. Dako LSAB kit (DAKO A/S, Carpinteria, Calif) after antigen retrieval by pressure cooking. After quenching in 3% hydrogen peroxide and blocking, the sections were incubated with primary antibodies for the aforementioned ECM proteins overnight at 4°C. Biotinylated secondary antibody and streptavidin conjugated to horseradish peroxidase were subsequently applied with color development with 3,3'-diaminobenzidine and hematoxylin counterstaining. Negative control slides in the absence of primary antibody were included for each staining. Samples were evaluated with both methods by 3 independent observers blinded to the register that matched specimens with patient clinical data, using a grading scale for semiquantification of staining, from none (0) to intense (4). Owing to the overall good correspondence between fluorescence and peroxidase assessments, each specimen was assigned 1 score (averaging the 6 scores from the 2 methods).
Assessment of SMC Density, Apoptosis, and Proliferation
Wall fragments from the concavity and convexity of the ascending aorta (n = 54) were washed in PBS, fixed in 10% buffered formalin, paraffin-embedded, and sliced in 4-µm serial sections. After deparaffinization, the ApopTag Plus Fluorescein In Situ Apoptosis Detection Kit (Chemicon, Temecula, Calif) was used, according to the manufacturer protocol. In brief, sections were pretreated with proteinase K for 15 minutes. Pre-equilibrated sections were covered with terminal deoxynucleotidyl transferase working solution and incubated for 1 hour at 37°C in a humidified chamber. The reaction was stopped by incubation with stop/wash buffer. After three washes with PBS, antidigoxigenin fluorescein isothiocyanate conjugate (Sigma-Aldrich) was applied to the slides for 30 minutes at room temperature. For characterization of apoptotic cells, sections were subsequently incubated with anti-smooth muscle 
-actin antibody (Sigma-Aldrich) for 1 hour at 37°C in a humidified chamber. After washes in PBS, rhodamine-conjugated secondary immunoglobulin G antibody (Jackson ImmunoResearch Laboratories, Inc, West Grove, Pa) was applied to the sections for 1 hour at 37°C. Cell nuclei were counterstained with 4',6-diamidino-2'-phenylindole (DAPI), and the sections were washed in PBS and mounted under a glass coverslip. The slides were examined with a fluorescence microscope (Leica Microsystems) by 3 independent observers blinded to the register matching specimens with patient clinical data: the number of SMCs in 1 mm2 (SMC density) and the rate of apoptotic SMCs (apoptotic index, AI) were determined counting 1000 nuclei in each section. For investigation of SMC proliferation, double immunostaining was performed (n = 24) with the aforementioned anti-actin antibody (Sigma-Aldrich) and primary rabbit polyclonal antibodies against the Ki-67 antigen (NovoCastra Laboratories Ltd, Newcastle upon Tyne, United Kingdom), previously unmasked by pressure cooking in 10-mmol citric acid, pH 6. Ki-67 is expressed during late G1, S, G2, and M phases of the cell cycle, not in early G1 and G0.12
Bcl-2-modifying Factor-Bcl-2 Coimmunoprecipitation and Bcl-2 Messenger RNA Quantification
To assess the presence and degree of matrix-dependent cytoskeleton-mediated proapoptotic signals in aortic dilations, we quantified the interaction of Bcl-2-modifying factor (Bmf) with Bcl-2. Bmf is a proapoptotic BH-3 only protein normally sequestered to the myosin V actin motor complex13: when released by actin cytoskeletal reorganization after altered matrix rigidity9-11,14 or cell-matrix detachment,9,11 it binds to Bcl-2, initiating apoptosis. The tissue fragments were fast frozen in liquid nitrogen and pulverized. The samples (n = 42) were suspended in a lysis buffer containing 50 mmol/L Tris-HCl (pH 7.4), 5 mmol/L ethylenediaminetetraacetic acid, 250 mmol/L NaCl, 0.1% Triton X-100 supplemented with proteases inhibitors (1 mmol/L dithiothreitol, 2 mmol/L phenylmethylsulfonyl fluoride, 2 µg/mL aprotinin, and 10 µg/mL leupeptin), incubated on ice for 30 minutes to obtain total cell lysate, and centrifuged at 14000g for 20 minutes. The protein concentration in the supernatant was determined with the BioRad Protein Assay (Bio-Rad Laboratories, Hercules, Calif). The lysates containing 300 µg of proteins were incubated with anti-Bcl-2 antibody (Santa Cruz Biotechnology) at +4°C overnight, followed by incubation with protein G agarose (Invitrogen Corporation, Carlsbad, Calif) for 3 hours. Immunoprecipitates were washed 3 times and collected beads were boiled in Laemmli loading buffer (Bio-Rad Laboratories). The presence of Bmf bound to Bcl-2 was analyzed by electrophoresis on 12% sodium dodecylsulfate-poliacrylamide gel and Western blot using anti-Bmf antibody (Santa Cruz Biotechnology).13 An incubation of tissue lysates with nonspecific immunoglobulin G at the same concentration was used as a negative control for immunoprecipitation, and the absence of signal in control samples confirmed specificity. An internal control sample was run on each gel for normalization. For corollary assessment of Bcl-2 expression, total RNA was isolated by lysis (n = 20; 3 normal aortas and 7 BAV-associated mild dilations) in TRIzol solution (GIBCO BRL, Invitrogen Life Technologies, Rockville, Md). After the yield and integrity control of each RNA sample, 2.5 to 5 µg of total RNA was reverse-transcribed by using the First-Strand cDNA Synthesis Kit (Amersham Pharmacia Biotech, Arlington Heights, Ill) with the random hexamer primers. The same volume (2 µL) of products from each sample was used for subsequent polymerase chain reaction (PCR) amplification with the primers reported in Appendix E1. Samples without complementary DNA served as negative controls for PCR amplifications. See Appendix E1 for the PCR program. The amplified products were analyzed by electrophoresis in 2% agarose gel containing ethidium bromide, and photographs were taken under ultraviolet illumination. Bcl-2 messenger RNA (mRNA) expression was quantified by densitometry scanning and normalized against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) controls.
Statistical Analysis
Paired t test (convexity vs concavity) and the Student t test (BAV vs TAV) were used for comparisons. One-way analysis of variance with Bonferroni post hoc correction was used for comparisons between normal, dilated, and aneurysmal aortas. Correlations were analyzed by computing the Pearson coefficient.
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-actin-positive cells was 0.07% ± 0.05% (P = .32 versus normal; Figure E1). Owing to limited tissue availability for experiments, no comparison between subgroups could be performed.
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Discussion |
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Early and Late SMC Changes
To our knowledge, only one previous report2 showed early apoptosis in the nonaneurysmal BAV aorta, although it included patients operated on for aortic stenosis, regurgitation, coarctation, and coronary artery disease in one group. However, in studies assessing aortic wall changes, patient samples should be homogeneous for valve function, inasmuch as important differences have been found between BAV stenosis and regurgitation in terms of epidemiology5 and morphologic/molecular features of ascending aortic dilation4: valve function can influence even the natural history of dilation.6 Other investigations on SMC apoptosis in BAV aortopathy analyzed only end-stage aneurysmal tissues.1,2
Our findings indicate that the cellular and extracellular processes underlying aortic enlargement are already operative in the normally sized or slightly dilated BAV aorta (mean diameter 3.8 cm), although limited to the convexity. The evidence of a "preclinical" aortopathy may add to the current debates on whether and how to concomitantly address the ascending aorta at the time of surgery for BAV stenosis.15 The recent studies on matrix metalloproteinases3 (MMPs), as well as gene mutational analyses,16 may potentially pave the way for development of new diagnostic and predictive strategies that may help to cope with this clinical challenge.
With increasing aortic dimensions (mean diameter 4.9 cm), ECM rearrangement at BAV convexity continued, whereas SMC density increased back to normal levels. A similar temporal pattern was observed in the TAV setting, although accompanied by a significant increment of AIs, in apparent contrast with the increase in cellularity. Also, Tang and coworkers17 have recently found comparable SMC density in aneurysms and nondilated aortas. Kirsch and colleagues18 observed higher SMC density in the maximal dilation area of TAV aneurysms than in the transition zone between normal aorta and maximal dilation, thus inferring a temporal pattern of SMC density changes concordant with our observations. However, neither one of those studies17,18 investigated SMC apoptosis and proliferation. Concomitant high AI and normal SMC density in our aneurysm specimens could not be explained by concurrent proliferation, since Ki-67 expression was not increased compared with normal. Thus, we suggest that the loss of noncellular components of the media may have quantitatively prevailed on SMC apoptotic loss, for faster progression of ECM breakdown, resulting in apparent normal SMC density, although the absolute cell number must have decreased. Although we could not calculate medial cross-sectional areas,17 the aortic media was significantly thinned, even with mean diameters smaller than in previous studies.17,18 On the other hand, a previous study showed medial cell proliferation by Ki-67 staining in aortic dissection,19 a condition that may, however, be subtended by different remodeling processes compared with poststenotic dilations.1
The differences emerging in the patterns of lesional maturation argue in favor of different mechanisms of early medial remodeling in BAV versus TAV: in BAV aortopathy, apoptosis may be part of the initiating events, whereas in the TAV setting, at least in a proportion of patients, its occurrence is delayed, possibly representing a mechanism, if not a consequence, of dilation itself.
Reciprocal Influences Between ECM and SMC in Aortic Remodeling
The features of ECM remodeling observed in this study deserve a comment in light of the known paradigms of ECM-SMC interplays.7,8 The increase in fibronectin with concomitant decrease in laminin suggests the constitution of a microenvironment that favors SMC phenotype modulation from the contractile to the synthetic phenotype.8 This suggestion is confirmed by the evidence that the glycoprotein tenascin-C, scarcely detectable in normal aortas, but typically produced by SMCs in synthetic phenotype,4,20 was expressed in aneurysms and also in the greater curvature of BAV-related mild dilations. Furthermore, other markers of synthetic phenotype have been found in medial degeneration of the ascending aorta.1 The more significant reduction in collagens and laminin in BAV versus TAV dilations is consistent with the greater increase in MMP-2 observed in BAV by Ikonomidis and coworkers.3 In our previous study,4 collagenolysis in BAV stenotic aorta was suggested by decreased collagen type I, as assessed by Western blot, despite normal expression of collagen type I mRNA. Indeed, tenascin and MMPs are tightly connected in vascular remodeling: tenascin is capable to activate MMPs and, in turn, proteolysed collagen type I stimulates tenascin production.20
In the present study, we sought to assess whether ECM changes in BAV aortopathy could exert a causative influence also on SMC apoptosis. Although promoting SMC survival and proliferation is the physiologic function attributed to tenascin in vessel development and response to injury,20 it has been shown that in conditions of MMP overexpression, enzymatic degradation of tenascin leads to the exposition of domains in its molecule that are proapoptotic for SMCs.21 Similarly, fibronectin is a survival factor for SMCs,7,8 although its proteolysis by plasmin and MMPs produces prodetachment/proapoptotic fragments.9 Therefore, the MMP repertoire typically expressed in the BAV aorta3 may convert a prosurvival ECM into a proapoptotic environment for SMCs. Notably, extrinsic proapoptotic cues are known to be transmitted within the cells through structural rearrangements of the actin cytoskeleton, so that changes in cell-matrix interactions are accompanied by cell shape changes (gross cell rounding, but also subtler disorders) as part of the causative mechanism of apoptosis ("amorphosis").11,22,23 To be able to interact with Bcl-2 and to promote apoptosis, Bmf must be released by its normal site, where it is thought to serve as a sensor of actin cytoskeleton integrity.13,14 Our finding of a significant increase in Bmf-Bcl-2 interaction in BAV convexity at an early stage of dilation development strongly suggests that rearrangements in SMC cytoarchitecture may be brought about by early ECM changes and, in turn, convey a proapoptotic signal. ECM-dependent apoptosis does not necessarily require cell detachment (anoikis proper): alterations of matrix geometrical organization or physical properties can trigger this mechanism of programmed cell death even without detachment.9-11,13 Indeed, we observed a reduction of Bcl-2 mRNA, whose expression is regulated also by matrix-dependent cytoskeletal changes.22,23 The fact that Bmf-Bcl-2 did not further increase in larger aneurysms, despite the increment in AI, suggests that late apoptosis, both in TAV aneurysms and in BAV concavity, may result from other pathways. Our study did not explore, for example, the apoptotic pathway of cytokine signaling, and the possible involvement of inflammatory mediators17,18 should be investigated in early versus late lesions. However, late apoptosis may be not a causative factor but rather a consequence of aneurysm growth itself, and another possible cause could be increased wall strain owing to enlargement and loss of elasticity.17 Apoptosis in response to cyclic strain has been shown to occur in well-differentiated contractile SMCs, but not in those that have undergone phenotype change24: consistently, we found no AI elevation in BAV aneurysm convexity, where a greater expression of ECM proteins promoting phenotype switch was observed.
A Pathogenetic Hypothesis
The asymmetrical spatial pattern of ECM and SMC changes uniquely found in early BAV dilations introduces, in the long-standing debate on the pathogenesis of BAV-related aortic disease, evidence in favor of a determinant or at least contributory role of hemodynamics. A BAV stenosis, being asymmetric in geometry, produces an eccentric jet yielding more severe flow alterations in the ascending aorta than TAV stenosis with similar gradients and valve areas.25 BAV-related turbulences have been shown to produce uneven wall stress distribution, with overload at the aortic right anterolateral wall (convexity).26 Conversely, a hypothetical inborn wall defect2 sufficient to cause dilation should produce a remodeling process uniformly involving the whole aortic circumference, which was denied by the present study. Thus, we hypothesize that altered flow (even though not necessarily a "clinically" altered flow25,26) could be either the triggering cause of early wall lesions or the factor required for local expression of a latent defect. Both in vitro and in vivo studies have shown SMC phenotype change,27 fibronectin and tenascin production,27 and increased MMP expression and activity28 to be elicited by undue biomechanical stress, as well as apoptotic SMC death, with reduced Bcl-2 expression,24 as found in the present study, and increased p53 expression,29 as found by Ihling and colleagues19 in medial degeneration. In our hypothesis, stress-induced early ECM changes unique to BAV convexity promote early SMC apoptosis, at least in part through Bmf-Bcl-2 interaction, leading to progressive, typically asymmetric aortic enlargement.
However, further work is needed to verify this theory. The possibility cannot be discarded that BAV might be associated with a congenital anomaly of some component of matrix signaling pathways, and flow disturbances at the convexity could merely accelerate locally the degenerative process, however destined to involve also the concavity within a longer time span.
Study Limitations
A first limitation of the present study concerns the reference control group ("normal aorta"): the most appropriate control subjects for comparison with patients with BAV aortopathy should have been the nonstenotic BAV with normal-sized aorta, a setting that was not represented in our surgical specimens. Second, the reason for the choice of Bmf-Bcl-2 measurement as the sign of proapoptotic cytoskeleton rearrangement was that Bmf release does not occur in response to other types of apoptotic stimuli in vivo.10,13 Cell-matrix detachment has never been demonstrated in medial degeneration; thus, our starting hypothesis was that altered matrix solidity could be rather responsible for proapoptotic signaling.11,13 However, whether cell anchorage is lost or not remains to be discerned, and to this scope, caspase 8 and integrins may represent interesting targets: caspase 8 activity increases after loss of integrin-mediated anchorage, but Bmf can be released without caspase 8 activation in the case of cytoskeleton rearrangement without detachment.14,22 Finally, smooth muscle -actin and other SMC markers can be expressed also by myofibroblasts, migrating from the adventitial layer to the media during vascular remodeling, for example, in response to mechanical injury.30 Thus, our study, as well as the previous ones using smooth muscle actin staining,1,2,17-19 could not differentiate myofibroblasts from SMCs in the media, and the assessment of the role of resident cell types other than SMCs awaits further study.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsAppendix E1References |
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Appendix E1 |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsAppendix E1References |
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The following primers of the Bcl-2 gene and the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) housekeeping gene were used for PCR (expected size of the amplification product):
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Footnotes |
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* PhD program, "Medical and Surgical Physiopathology of the Cardio-Respiratory System and Associated Biotechnologies," Second University of Naples, Italy. 
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsAppendix E1References |
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P < .05 BAV versus normal (P = .016 for collagen type I; P = .008 for fibronectin) and versus TAV dilation (P = .008 for collagen type I; P = .037 for fibronectin); °P < .05 aneurysm versus respective dilation (P = .007 for collagen type I in BAV; P = .03 and P = .01 for collagen type I in TAV; P=.002 for tenascin in BAV); P < .01 for all differences between convexity and concavity in BAV. P < .05 (not significant) for all other comparisons. ECM, Extracellular matrix; TAV, tricuspid aortic valve; BAV, bicuspid aortic valve.
