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Departments of 1Cardiology, 2Cardiothoracic Surgery, 3Molecular Cell Biology, and 4Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht and Maastricht University, Maastricht; 5Department of Anatomy and Embryology, Experimental and Molecular Cardiology Group, Academic Medical Centre, University of Amsterdam, Amsterdam; and 6Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands
Submitted 13 April 2006 ; accepted in final form 5 January 2007
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1D-integrin, melusin, Akt, GSK3, muscle LIM protein (MLP), four-and-a-half LIM protein 2 (fhl2), desmin, and calpain. Upon AVB, increased ejection strain (0.29 ± 0.01 vs. 0.13 ± 0.02, SR) and end-diastolic stress (4.8 ± 1.1 vs. 2.7 ± 0.4 kPa) dominated mechanical changes. Brain natriuretic peptide plasma levels were correspondingly high (33 ± 4 vs. 19 ± 1 pg/ml, SR). 1D-Integrin protein expression increased chronically after AVB. Melusin was temporarily overexpressed (+33 ± 9%, 3 days AVB vs. SR), followed by elevated ratios of phosphorylated (P)-Akt to Akt and P-GSK3 to GSK3 (+26 ± 6% and +30 ± 8% at 10 days AVB vs. SR). These changes corresponded to peak hypertrophic growth at 3 to 10 days. MLP increased gradually to maxima at chronic AVB (+36 ± 7%). In contrast, fhl2 (–22 ± 3%, 3 days) and desmin (–30 ± 9%, 10 days AVB) transiently declined but recovered at chronic AVB. Calpain protein expression remained unaltered. In conclusion, volume overload after AVB causes a transient compromise of cytoskeletal integrity based, at least partly, on transcriptional downregulation. Subsequent cytoskeletal reorganization coincides with the upregulation of melusin, P-Akt, P-GSK3, and MLP, indicating a strong drive to compensated hypertrophy.
hemodynamics; myofiber mechanics; serial intramural ventricular biopsies; cardiomyocyte remodeling; ventricular hypertrophy
Recently, we described the time course of left ventricular (LV) myocardial mechanics in dogs with bradycardia-induced volume overload due to complete atrioventricular block (AVB) (11). Early after AVB, increased end-diastolic myofiber stress and ejection strain are imposed on the myocardium, and they coincide with peak hypertrophic growth, suggesting their role as primary stimuli for mechanotransduction.
Besides ventricular hypertrophy, the AVB model is characterized by important electrical, contractile, and structural remodeling, yet an exact relation with mechanical overload is currently unknown.
In the present study, we examined the time-dependent effects of increased load on myocardial remodeling during AVB, focusing specifically on the expression of key proteins involved in mechanotransduction and cytoskeletal integrity, i.e., laminin, 1D-integrin, 1D-integrin-interacting protein melusin, Akt (protein kinase B), GSK3, muscle LIM protein (MLP), four-and-a-half LIM protein 2 (fhl2), and desmin. Serial analysis of myofiber mechanics was combined with the determination of plasma levels of brain natriuretic peptide (BNP), a biochemical marker of load. Repetitive sampling of intramural LV biopsies was applied to analyze protein expressions in individual dogs over time.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Model of Complete Atrioventricular Block
Twenty adult mongrel dogs of either sex weighing 25 ± 1 kg were used. After dogs were fasted overnight, premedication (1 ml/10 kg im Acetadon containing 1.5 mg/ml acepromazine, 4 mg/ml methadone, and 0.6 mg/ml atropine) was administered. Complete anesthesia was induced by thiopental sodium (20 mg/kg iv) and maintained with halothane (0.5–1%) and O2-N2O (1:2). AVB was induced by radiofrequency catheter ablation of the His bundle. Animals were studied serially at sinus rhythm (SR; control) and at 0, 3, 10, and 35 days AVB. A standard six-lead ECG was registered. After the animals were killed (35 days AVB), the hearts were excised and weighed.
LV Mechanics
LV mechanics were quantified as myofiber stress and strain by applying serial transthoracic echocardiography synchronized with recordings of LV cavity pressure using a validated mathematical model (2), as we have recently described in detail (11). Plasma levels of BNP were determined in peripheral venous blood, collected in chilled EDTA tubes, centrifuged (1,600 g, 10 min, 4°C), and stored at –80°C until measured in duplicate by a radioimmunoassay specific for canine BNP-32 (Phoenix Pharmaceuticals, Mountain View, CA).
Serial Percutaneous Sampling of LV Intramural Biopsies
Intramural LV needle biopsies were taken serially in dogs at SR and after 3, 10, and 35 days AVB. A 16-gauge biopsy needle (Acecut, TSK Laboratory) was percutaneously inserted into the apicolateral LV wall, under fluoroscopic guidance. At least two samples (
10 mm3) were obtained per experiment. Tissue quality was optimal in most biopsies (>98%). All animals were followed by transthoracic echocardiography after biopsy sampling to exclude cardiac tamponade, although in our experience the closed-chest approach is generally uncomplicated (>95%) and fatal outcome is rare (<3%). Such complications did not occur in this study.
Light and Electron Microscopy
For light (LM) and electron microscopy (EM), biopsies were processed and analyzed as described before (4). Briefly, tissue was fixed in 3% glutaraldehyde and embedded in epoxy resin. LM analysis was performed on periodic acid-Schiff (PAS)-/Toluidine blue-stained sections to depict cardiomyocyte glycogen content, sarcomeres, mitochondria, and nuclei. PAS positivity and absence of contractile filaments in >10% of the cell surface area of transversely sectioned cardiomyocytes were considered abnormal.
Immunohistochemistry
Indirect immunohistochemistry was performed on briefly fixed tissue (3% glutaraldehyde or 3.7% formaldehyde) using primary antibodies directed against desmin (DE-R-11, 1:10) (Dako Cytomation, Glostrup, Denmark), MLP (1:80) (1), vimentin (K36, 1:10) (Frans C. Ramaekers, Maastricht University), and laminin (L9393, 1:150) (Sigma, St. Louis, MO). Specific labeling was visualized using appropriate secondary antibodies applying immunoperoxidase or immunofluorescence techniques. Nuclei were stained using Mayers hemalum or propidium iodide. For negative control, the primary antibodies were omitted. Immunofluorescent labeling was analyzed using confocal laser scanning microscopy (Bio-Rad MRC600, Bio-Rad, Hercules, CA).
Real-Time PCR
Total RNA was isolated from the biopsies with the use of the RNEasy Mini kit (Qiagen/Westburg, Leusden, The Netherlands). Fluorescence-based kinetic real-time PCR was performed with a LightCycler system (Roche Diagnostics, Almere, The Netherlands), and amplicons were quantified relative to the constitutively active 18S rRNA by using the LinRegPCR method (31).
Western Blotting
Total homogenates were derived from unfixed cryosections (5 µm) dissolved for 30 min on ice in lysis buffer (62 mmol/l Tris, 1.25 mmol/l EDTA, 2% Nonidet P-40, 2.5 mmol/l phenylmethylsulfonyl chloride, 12.5 mg/ml leupeptin, 12.5% glycerol, 100 mg/ml aprotinin, 0.5 mM sodium orthovanadate, and 2.3% SDS) and sample buffer for 4 min at 95°C (62 mmol/l Tris, 2.3% SDS, 10% glycerol, 5% -mercaptoethanol, and 0.05% bromophenol blue). Equal amounts of total protein (7.5–30 µg/lane), determined by protein assay (Bio-Rad), were loaded on 10% SDS-PAGE gels, transferred to nitrocellulose membranes, and controlled by Coomassie brilliant blue, Ponceau S staining, and GAPDH immunoblotting. Membranes were blocked in BSA (3%, 1 h) in Tween buffer (TWB), containing PBS and Tween 20 (0.05%), and incubated with the primary antibody in BSA (0.5%, 1 h) against desmin (DE-R-11, 1:5,000), 1D-integrin (2B1, 1:100) (Mubio, Maastricht, The Netherlands), melusin (1:500) (7), MLP (1:500) (1), fhl2 (1:500) (24), Akt (9272, 1:1000), phosphorylated (P)-Akt (Ser473, 1:1000), GSK3 (9315, 1:1000), P-GSK3 (Ser9, 1:1000) (Cell Signaling Technology, Danvers, MA), and the regulatory subunit of calpain I and II (P1, 1:1100) (Chemicon, Temecula, CA). After blots were washed in TWB, they were incubated (1 h) using the appropriate secondary antibodies, washed again, and visualized on X-ray films (Fujifilm, Rotterdam, The Netherlands) with enhanced chemiluminescence (Amersham Biosciences, Amersham, UK). Densitometric quantification was performed with Quantity One software using a GS-800 scanner (Bio-Rad). All immunoblots were performed in duplicate.
Statistical Analysis
Data are presented as means ± SE. Data were compared by using Student's t-test for unpaired or paired data. Serial data were tested by repeated-measures ANOVA using Bonferroni's post test comparison. Differences were considered statistically significant if P < 0.05.
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RESULTS |
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For information regarding hemodynamic changes after AVB in this study, we refer to Table 1. Consistent with our previous study (11), LV mechanical load was characterized by early increases of end-diastolic myofiber stress (4.8 ± 1.1 vs. 2.7 ± 0.4 kPa at SR, P < 0.01) and ejection strain [0.29 ± 0.01 vs. 0.13 ± 0.02 (no units) at SR, P < 0.01]. End-diastolic stress normalized after 35 days AVB (Fig. 1, A and B). Systolic myofiber stress did not change during AVB [37.3 ± 3.6 vs. 38.0 ± 4.3 kPa at SR, P = not significant (NS)].
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Dynamic Cardiomyocyte Remodeling After AVB
The presence of cardiac hypertrophy was confirmed at autopsy after 35 days. Total heart weight (270 ± 12 g) and heart weight-to-body weight ratio (10.7 ± 0.6 g/kg) were larger than in a matching control population of dogs with SR (202 ± 12 g and 8.0 ± 0.4 g/kg, respectively; both P < 0.05).
Key proteins involved in mechanotransduction.
Western blot analysis revealed a significant increase of 1D-integrin expression after AVB when compared with SR (Fig. 2A), whereas its extracellular ligand laminin did not alter (Fig. 3A). Time-dependent expression of melusin, a protein directly interacting with the cytoplasmic domain of 1D-integrin at the Z disk, was characterized by an early peak at 3 days AVB (+33 ± 9% vs. SR, P < 0.05), which gradually declined thereafter (Fig. 2B).
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was phosphorylated along with Akt, reaching peak values of the P-GSK3-to-GSK3 (P-GSK3/GSK3) ratio at 10 days (+30 ± 8% vs. SR, P < 0.05) (Fig. 4B). This higher degree of Akt and GSK3 phosphorylation was transient, because the P-Akt/Akt and P-GSK3/GSK3 ratios at 35 days AVB were not different from control.
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1D-integrin-melusin, showed divergent expression patterns during AVB. MLP gradually increased to maxima at chronic AVB (+36 ± 7% at 35 days vs. SR, P < 0.01; Fig. 2C), whereas fhl2 exhibited an early decline (–22 ± 3% vs. SR, P < 0.01) (Fig. 2D). Immunohistochemical studies revealed that, during AVB, MLP expression increased throughout the cytoplasm and was also prominently expressed in the nucleus (Fig. 5). The temporal expression of MLP correlated highly with increasing echographic LV mass (in grams) over the weeks after AVB (Fig. 6). In addition, we found a good correlation between the expression of melusin, the ratiometric expression of P-Akt/Akt and P-GSK3/GSK3, and the degree of hypertrophic growth (LV mass increase per time in g/day; Fig. 6).
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1D-integrin-interacting extracellular protein laminin (Fig. 3A) and the fibroblast intermediate filament vimentin (Fig. 3B). Micromorphometry of cardiomyocyte cross sections showed comparable diameters between SR (23 ± 1 µm), 10 days (24 ± 1 µm, P = NS), and 35 days AVB (25 ± 1 µm, P = NS), supporting previous data showing predominant cellular lengthening after AVB (11, 37). Cytoskeletal integrity was further explored by analysis of the intermediate filament desmin (Fig. 7). During SR, quantitative analysis of mRNA and protein expression showed a downregulation at 3 and 10 days AVB and subsequent normalization (Fig. 7, A and B). Desmin immunolabeling was in agreement with the mRNA and protein data and exhibited a normal cross-striated pattern at the Z line and prominent expression at the intercalated disk. At 3 and 10 days AVB, desmin labeling at the intercalated disk clearly decreased compared with the Z-line labeling. After 35 days, desmin expression was restored, particularly at the intercalated disks (Fig. 7, C and D).
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To quantify these abnormalities by LM, we performed PAS staining to depict the glycogen accumulation observed during EM analysis. The number of abnormal glycogen-stuffed cardiomyocytes per microscopic section area was increased at 10 days AVB (5 ± 2% vs. 2 ± 1% at SR, P < 0.05) and had normalized again at 35 days AVB (Fig. 3E).
Finally, to examine whether the Ca2+-dependent protease calpain could be involved in the loss of cytoskeletal and contractile elements, serial Western blot analyses of the regulatory subunits of calpain I and II were performed, which showed an unaltered protein expression throughout the experimental period.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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In the present study we have confirmed previous results (11) that both end-diastolic stress and ejection strain are driven to maximal amplitudes within the first week of AVB. As a first new finding, this acute and enduring volume overload is reflected by a parallel release of the load biomarker BNP. Absolute plasma levels of BNP after AVB were comparable to those in dogs with compensated overload of different cause, varying roughly between 25 (16) and 40 pg/ml (3). Correlation analysis suggests that BNP release after AVB is mainly driven by systolic ejection strain. In vitro studies support that mechanical stimuli applied during systole can be even more capable of increasing BNP transcription than diastolic stimuli (40). Nevertheless, diastolic load may well contribute to the BNP release after AVB, despite a weak temporal correlation. Diastolic mechanical stimuli have been shown to trigger BNP release in other animal models (15) and in humans with overload (25).
Dynamic Expression of Key Mechanotransduction Proteins After AVB
Key proteins located at the Z-disk level have been proposed to sense and transduce mechanical stimuli (13, 22, 30). Among those, integrins are obvious candidates that span the sarcolemma (32). In cardiomyocytes, 1D-integrin is dominantly expressed (36) and has been shown to be relevant for mechanotransduction under basal (i.e., normal load) conditions and pathological overload (33). Its increased expression has been observed during hypertrophy after adrenergic stimulation in vitro (28, 32) and during chronic aortic constriction in mice (5). During AVB, 1D-integrin expression was increased from 3 days onward. This early and sustained upregulation is in line with findings in other models of hypertrophy (5, 28, 32). Interestingly, the immunoexpression of laminin, the primary extracellular 1D-integrin ligand (32), and vimentin, a fibroblast marker, were found unaltered (Fig. 3B). These findings suggest that the cardiomyocyte protein 1D-integrin, and not components of the extracellular matrix, is among the first upstream elements ("initiators") activated by mechanical stimuli in this model.
At its cytoplasmic domain, 1D-integrin binds to melusin, a striated muscle-specific protein involved in mechanical signaling, promoting cardiac compensation and preventing failure (6, 10). The latter was concluded from experiments in mice after aortic constriction. Melusin-null animals exhibited less hypertrophy and more rapid LV dilation and failure (6), whereas transgenic mice overexpressing melusin showed a prolonged phase of compensated hypertrophy in the absence of fibrosis as compared with wild-type animals (10). In wild-type mice, aortic constriction led to an overexpression of melusin after 1 wk during compensated hypertrophy, whereas melusin returned to baseline, when LV dilation and impaired contractility ensued after 12 wk (10). Interestingly, we found a similar temporal expression pattern of melusin after AVB, with an upregulation at 3 days AVB and a gradual decline thereafter. It is tempting to speculate that, early after AVB, increased melusin expression promotes compensated hypertrophy through mechanisms that remain to be elucidated. This procompensatory effect of melusin appeared closely related to the stimulation of hypertrophic growth (6), which could also hold for the AVB model, where melusin overexpression coincides with measures of peak hypertrophic growth (Fig. 6A).
In downstream hypertrophic signaling, melusin is involved in the phosphorylation of Akt and GSK3 in response to mechanical load (6, 10). We found that the overexpression of melusin coincided with the ratiometric increase of P-Akt/Akt and P-GSK3/GSK3 during a phase of maximal mechanical load (Fig. 1, A and B) and hypertrophic growth (Fig. 6). Phosphorylation inhibits the constitutively active antihypertrophic effect of GSK3 and, thereby, likely stimulates different transcriptional events (14).
MLP is another key Z-disk protein involved in mechanotransduction and -sensing. It interacts with 1D-integrin via 
-actinin, is associated with the actin cytoskeleton, and was recently identified as a crucial element of the "cardiac mechanical stretch sensor machinery" consisting of a MLP-titin-telethonin protein chain (22). It has been postulated that a defective chain, as in MLP-null mice and a subset of patients with reduced MLP levels and heart failure (41), leads to dilated cardiomyopathy due to malfunctioning mechanosensing (22). In dogs with AVB, MLP expression gradually increased to significant levels at chronic AVB, which suggests that the MLP-titin-telethonin chain is likely not defective in this model. This is further supported by the finding of BNP release after AVB, which requires, according to a recent study (22), an intact MLP-titin-telethonin chain as prerequisite for BNP increase during mechanical overload. It has recently been shown that MLP plays an important role in the stimulation of cardiomyocyte hypertrophy via activation of the calcineurin-nuclear factor of activated T-cell pathway (17, 18). MLP may act as a scaffold protein to facilitate sarcomere assembly (17) and stimulate further downstream signaling (22). These findings of a procompensatory role of MLP in other models of hypertrophy (17, 18, 22) are in agreement with the high correlation of the temporal expression patterns of MLP and increased LV mass after AVB (Fig. 6). We found that, after AVB, MLP expression increased in both the cardiomyocyte cytoplasm and nucleus (Fig. 5). These subcellular localizations have been described for MLP and other LIM proteins (21). Nuclear relocation in conjunction with MLP downregulation has been linked to a "phenoconversion" toward heart failure (12). However, in our model with compensated hypertrophy, the nuclear translocation is associated with increased MLP levels, suggesting increased transcriptional activity, as also postulated for other LIM proteins (21).
The other Z-disk LIM domain protein that we studied, fhl2, also colocalizes with 1D-integrin, -actinin, and the actin cytoskeleton and is relevant for cardiomyocyte differentiation and myofibrillogenesis (20), as described for MLP. In contrast, fhl2 expression during AVB is transiently reduced around 10 days of AVB. This implicates a different role for fhl2 in the AVB model, which should be analyzed in more detail in future experiments. Importantly, fhl2 and MLP have a divergent protein structure, which is compatible with a different functional role (21). In contrast with MLP, fhl2 is regarded as a repressor of hypertrophy (29). It interacts with ERK2, an element of the MAP kinase signaling pathway. Hypertrophic responses induced by adrenergic stimulation, and mediated via ERK2, are partially antagonized by fhl2, which attenuates transcription (29). In line with this finding, fhl2-null mice, which exhibit a normal cardiac phenotype, show increased hypertrophic growth after catecholamine infusion, supporting repressor-like activity of fhl2 in the overloaded myocardium (23). ERK2 interacts with fhl2, but it does not interact with MLP, which underscores the protein-specific action of LIM proteins (29). The early transient downregulation of fhl2 after AVB coincides with an enhanced adrenergic tone (34) and maximal hypertrophic growth in the first 10 days after atrioventricular block. It could well be that hypertrophy is partly caused by enhanced adrenergic stimulation and mediated via MAP kinase/ERK2. The latter pathway could be incompletely repressed by the fhl2 reduction at this stage, promoting hypertrophy.
Transitory Changes of Cytoskeletal Elements After AVB
The depletion of sarcomeres and glycogen accumulation at 10 days AVB was similar but less extensive than reported in chronic hibernating myocardium (30%) (4). These morphological changes have been interpreted as signs of myocardial dedifferentiation (4). Interestingly, glycogen accumulation after AVB coincided with the ratiometric increase of P-GSK/GSK, which interacts with glycogen synthase, promoting glycogen synthesis and accumulation (14). Whether this observation is a purely metabolic phenomenon or a sign of beneficial cardiomyocyte remodeling remains to be elucidated.
The critical changes of the early phase after AVB are further characterized by the transient downregulation of desmin, which is the most important intermediate filament in cardiomyocytes and essential for their structural integrity and function, as recently reviewed (9). It forms a scaffold that interconnects adjacent myofibrils at the Z disks, serving as a physical link between the sarcolemma, cytoskeleton, and the nuclear envelope (9, 22, 30). A transient downregulation of desmin early during acquired mechanical overload has not been reported in the literature, but it could be a consequence of the abrupt mechanical impact of AVB exhibiting aspects of mild heart failure. In ventricular hypertrophy, desmin expression has been reported to be either unaltered (35) or increased (19, 38), but from studies in desmin knockout mice it has become clear that the absence of desmin is associated with cardiac hypertrophy and failure (9, 26). Our data suggest that the reduced desmin expression is regulated at the transcriptional level. We could not find a dominant role for calpain as a posttranslational modifier, which has been suggested with respect to the depletion of sarcomeres (8) and desmin disintegration (27), although we have only analyzed protein levels of the regulatory subunit of calpain I and II and not its protease activity, nor other proteases.
Importantly, during chronic AVB the degree of sarcomere depletion, glycogen accumulation, and total desmin content had normalized and desmin was even upregulated in a subset of dogs, especially at the intercalated disk. Since contractile activity has been reported to increase desmin expression by increased gene transcription (39), it could well be that the persistently high levels of ejection strain contribute to the normalization of desmin expression in the chronic phase of AVB.
Conclusions
The mechanical load acutely imposed on the ventricular myocardium after AVB causes a transient compromise of cytoskeletal integrity. This is based, at least partly, on transcriptional downregulation. By yet unknown molecular mechanisms, the dog with AVB is able to prevent serious disruption of sarcomeric elements and further downregulation of the important intermediate filament protein desmin. Toward chronic AVB a gradual structural reorganization and a strong drive to functionally compensated hypertrophy are attended by the early upregulation of melusin and MLP, known as procompensatory proteins in other models of ventricular hypertrophy and failure.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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1D-integrin and FAK are involved in cardiac myocyte hypertrophic response pathway. Am J Physiol Heart Circ Physiol 279: H2916–H2926, 2000.This article has been cited by other articles:
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  M. Yoshida, E. Sho, H. Nanjo, M. Takahashi, M. Kobayashi, K. Kawamura, M. Honma, M. Komatsu, A. Sugita, M. Yamauchi, et al. Weaving Hypothesis of Cardiomyocyte Sarcomeres: Discovery of Periodic Broadening and Narrowing of Intercalated Disk during Volume-Load Change Am. J. Pathol., February 1, 2010; 176(2): 660 - 678. [Abstract] [Full Text] [PDF]
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 E. Bovill, S. Westaby, A. Crisp, S. Jacobs, and T. Shaw Reduction of four-and-a-half LIM-protein 2 expression occurs in human left ventricular failure and leads to altered localization and reduced activity of metabolic enzymes J. Thorac. Cardiovasc. Surg., April 1, 2009; 137(4): 853 - 861. [Abstract] [Full Text] [PDF]
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 A. L. Baggish, K. Yared, F. Wang, R. B. Weiner, A. M. Hutter Jr., M. H. Picard, and M. J. Wood The impact of endurance exercise training on left ventricular systolic mechanics Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1109 - H1116. [Abstract] [Full Text] [PDF]
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f; A), ejection strain (
ef,ej, B), and plasma levels of brain natriuretic peptide (BNP; C) are shown. Changes of ejection strain (D, right), and not of end-diastolic stress (D, left), correlate well with altering BNP plasma levels. *P < 0.05 vs. sinus rhythm (SR); 
P < 0.05 vs. 3 days AVB.
