© 1999 American Heart Association, Inc.
Integrative Physiology |
Remodeling of Cell-Cell and Cell–Extracellular Matrix Interactions at the Border Zone of Rat Myocardial Infarcts
From the Department of Pathology and Cell Regulation (T.M., M.O., S.M., T.T.) and Second Department of Surgery (T.M., S.M., Y.W., T.O.), Kyoto Prefectural University of Medicine; Department of Anatomy (K.F.), Faculty of Medicine, Kyoto University; and Louis Pasteur Center for Medical Research (Y.Y.), Kyoto, Japan.
Correspondence to Tetsuro Takamatsu, Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto, 602-0841 Japan. E-mail ttakam{at}basic.kpu-m.ac.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—At the border zone of myocardial infarcts, surviving cardiomyocytes achieve drastic remodeling of cell-cell and cell–extracellular matrix interactions. Spatiotemporal changes in these interactions are likely related to each other and possibly have significant impact on cardiac function. To elucidate the changes, we conducted experimental infarction in rats and performed 3-dimensional analysis of the localization of gap junctions (connexin43), desmosomes (desmoplakin), adherens junctions (cadherin), and integrins (ß1-integrin) by immunoconfocal microscopy. After myocardial infarction, changes in the distribution of gap junctions, desmosomes, and adherens junctions showed a similar but nonidentical tendency. In the early phase, gap junctions almost disappeared at stumps (longitudinal edges of cardiomyocytes facing the infarct), and, although desmosomes and adherens junctions decreased, they still remained. In the healing phase, at stumps, connexin43, desmoplakin, and cadherin were closely associated between multiple cell processes originating from a single cardiomyocyte. Electron microscopy confirmed the presence of junctional complexes between the cell processes. ß1-Integrin at the cell process increased during the formation of papillary myotendinous junction–like structures. Abnormal localization of connexin43 was often accompanied by desmoplakin and cadherin on lateral surfaces of surviving cardiomyocytes. These findings suggested that remodeling of gap junction distribution was closely linked to changes in desmosomes and adherens junctions and that temporary formation of intracellular junctional complexes was an element of the remodeling of cell-cell and cell–extracellular matrix interactions after myocardial infarction. Moreover, the remodeling of the intercalated disk region at the myocardial interface with area of scar tissues was associated with the acquisition of extracellular matrix and ß1-integrin.
Key Words: cell junction • intercalated disk • myocardial infarction • remodeling • extracellular matrix
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Adult mammalian cardiomyocytes have only a limited regenerative potential. Once myocardial infarction occurs, infarcted myocardium undergoes a progressive sequence of changes consisting of ischemic coagulative necrosis, followed by inflammation and replacement with scar tissues. During the sequence, surviving cardiomyocytes have to adapt to an unfavorable environment, including ischemia, and inadequate adaptation results in ventricular remodeling. At the border zone of myocardial infarcts, viable cardiomyocytes undergo drastic reorganization of cell-cell and cell–extracellular matrix (ECM) interactions as they lose cell-cell connections because of the death of neighboring cardiomyocytes and subsequently anchor to scar tissues.
The intercalated disk is a unique structure of cardiomyocytes characterized by a grouping of 3 specialized cell-cell junctions; gap junctions, desmosomes, and adherens junctions.1 Gap junctions facilitate conduction of the cardiac impulse so that the whole heart behaves electrically as a syncytium, whereas desmosomes and adherens junctions ensure transmission of the traction generated by the individual cells throughout the myocardium.
In the ischemic heart, several studies have shown the remodeling of gap junctions by studying for connexin43 (Cx43), a major cardiac gap junction protein.2 3 4 5 We have reported the formation of cell processes in cardiomyocytes facing the infarct and the expression of Cx43 in these processes.5 The abnormality in gap junction distribution has been suggested to be one factor in arrhythmogenesis after myocardial infarction.6 Although gap junctions are closely associated with desmosomes and adherens junctions in the normal heart,7 8 few studies have been performed on spatiotemporal changes in desmosomes and adherens junctions after myocardial infarction, which potentially bear importance for the remodeling of gap junctions.2 3 4 9
Apart from intercellular junctions, ECM plays a vital role in force transmission throughout the myocardium.10 11 ECM significantly contributes to heart development and cardiac function through integrin-mediated cell-ECM interactions. After myocardial infarction, surviving cardiomyocytes facing the infarct lose their neighboring cells with which intercalated disks have originally formed, leaving blunt-ended stumps in direct contact with ECM.12 13 ß1-Integrin is very likely to play an important role in this interaction, because it is the predominant ß-subunit isoform of adult myocardial integrins11 14 15 that are involved in forming cell-surface receptors for various ECM components.
We have postulated the following hypotheses about the remodeling of cell-cell and cell-ECM interactions after myocardial infarction. Firstly, the remodeling of gap junctions after myocardial infarction is linked to changes in desmosomes and adherens junctions. Secondly, remodeling of the intercalated disk region at the myocardial interface with scar tissues requires acquisition of ECM components and integrins. To examine these hypotheses, we analyzed in detail spatiotemporal changes of gap junctions, desmosomes, adherens junctions, and integrins in cardiomyocytes by immunoconfocal microscopy and electron microscopy at the border zone of myocardial infarcts in rats.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Myocardial infarction was induced in 98 male Wistar rats (9 weeks old) by ligation of a branch of the left coronary artery as previously described.5 In the sham-operated group, the ligature was not tightened. Hearts after coronary ligation at various times (6, 12, 24, and 48 hours, and days 3, 4, 8, 15, 30, and 60 postligation) were fixed by perfusion and subsequent immersion with 2% paraformaldehyde in 0.01 mol/L PBS and frozen in liquid nitrogen. For immunohistochemistry of ß1-integrin, hearts were frozen without fixation.
The following antibodies were used: rabbit polyclonal antibody to Cx43 (Zymed Laboratories), mouse monoclonal antibody (mAb) to Cx43 (Chemicon), mouse mAb to desmoplakin I+II (Boehringer Mannheim), mouse mAb to pancadherin (Chemicon), rabbit polyclonal antibody to laminin (ICN Biomedicals), and hamster mAb to ß1-integrin.16 The antibodies against mouse IgG were adsorbed against normal rat serum. Texas Red (TR)-X–labeled phalloidin (Molecular Probes) was used for detection of F-actin. Serially sliced 20-µm-thick frozen sections were fixed with ethanol or acetone, dried, and rinsed in 5% skim milk in PBS, before washing in 0.1% Triton X-100 in PBS (15 minutes). Double-immunolabeling was performed using 2 of the above primary antibodies and FITC- and TR-labeled secondary antibodies. Negative controls in which one of the primary antibodies was excluded were performed to rule out cross-reactivity.
Immunolabeled sections were observed with a confocal laser scanning microscope (FluoView, Olympus). All figures were transverse optical sections of the left myocardium in which the cardiomyocytes were longitudinally sectioned. In the following, we use the terms "borderline" and "vicinity" to discriminate cells located differently with reference to the infarct as previously described.5
For morphometry, each confocal image was collected using an oil-immersion objective lens (PlanApo x60, numerical aperture=1.4, Olympus) and one-time zooming (field, 265x200 µm2). We classified longitudinal cell boundaries into 3 categories according to their sites with reference to the infarct, ie, those between cells or sites in each of the 3 following categories: infarcted cardiomyocytes (I), stumps (S), and vicinity cardiomyocytes (V). Each longitudinal cell boundary was enclosed manually, and the immunopositive area in the enclosed field and cell width at each cell-cell and cell-matrix boundary were measured. Because the optical section thickness is fixed and intercalated disks were randomly cross-sectioned in our samples, the mean of immunopositive area/cell width reflects the amount of junctional proteins per unit area of en face–viewed intercalated disks.17 18 All data were converted so that the mean of each datum on Cx43, desmoplakin, and cadherin of the sham category was 100% (total, 1119 readings). Data were analyzed by 2-factor factorial ANOVA, and significant differences were defined using the Scheffé test. The expression of ß1-integrin at stumps was compared with that at the myotendinous junction (MTJ) of sham-operated left ventricular papillary muscles.
For electron microscopy, hearts with/without arrest by perfusion of cardioplegic solution19 were fixed by perfusing 3% glutaraldehyde and 2% paraformaldehyde in 0.1 mol/L phosphate buffer and embedded in epoxy resin (Taab). Ultrathin sections were examined under an electron microscope.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Confocal Immunohistochemistry
Left Ventricles and Papillary Muscles of Sham-Operated Rats
Double-labeling using anti-Cx43 and either anti-desmoplakin or anti-cadherin antibodies showed that Cx43, desmoplakin (Figure 1A
), and cadherin were mainly closely
localized at longitudinal termini of cardiomyocytes in
sham-operated left ventricle. Double-labeling using
anti–ß1-integrin and anti-laminin demonstrated
that ß1-integrin was localized just inside the
laminin sheath around cardiomyocytes in a dotted pattern.
Neither ß1-integrin nor laminin was observed at
the intercalated disk.
|
, vessel wall. C and D, Double-labeling for either Cx43
(FITC) (C) or desmoplakin (FITC) (D) and actin (TR, phalloidin [Ph]).
Desmoplakin signals of infarcted cardiomyocytes are
agglomerated and are stronger than Cx43 signals. E and F,
Double-labeling for Cx43 (FITC) and either desmoplakin (TR) (E) or
cadherin (TR, Cad) (F). Cx43 signals nearly disappear at the stump. G,
Double-labeling for ß1-integrin (FITC) and laminin (TR).
ß1-Integrin signals are weakly expressed at the stump
(arrowhead). All figures are of the same magnification. Bar=20
µm.
Cardiomyocytes terminate on collagenous connective tissue in the
chordae tendineae at papillary MTJs. No immunofluorescent dots
of these junctional proteins were observed on the MTJ where
spindle-shaped cardiomyocytes were facing connective
tissues (data not shown). ß1-Integrin was
densely localized at the MTJ with laminin-forming sheaths around the
cardiomyocytes (Figure 1B
).
Postligation 6 to 48 Hours
By 6 to 12 hours postligation (Figure 1C and 1D), although
signals for Cx43, desmoplakin, and cadherin at the intercalated disks
were observed in the infarct zone, their normal distribution was lost,
ie, scattered and/or agglomerated. Among the 3 junctional proteins, the
number of Cx43 signals significantly decreased compared with those of
other proteins in the infarct. At stumps and cell borders of vicinity
cardiomyocytes, the expression of Cx43, desmoplakin, and
cadherin moderately decreased.
By 24 to 48 hours postligation, the expression of Cx43 markedly
decreased to <5% of the levels of sham-operated hearts, whereas those
of desmoplakin and cadherin remained at a similar level observed at 6
hours postligation at stumps (Figure 1E and 1F). In the infarct,
expressions of Cx43, desmoplakin, and cadherin were greatly diminished,
whereas those of vicinity cardiomyocytes decreased
moderately. The laminin sheath became discontinuous in the infarct, and
at stumps, ß1-integrin was weekly expressed
accompanied by a small amount of laminin (Figure 1G).
Days 3 to 90 Postligation
On day 3 postligation, the localization of desmoplakin and
cadherin at stumps approximated that at 48 hours. However, the
distribution of these proteins was scattered compared with those at 48
hours. Cx43 signal was very low at stumps.
On day 4 postligation, TR-phalloidin staining demonstrated that the
stumps began to extend fine cytoplasmic cell processes toward the
infarct (Figure 2A and 2B). Small
immunofluorescent spots of Cx43, desmoplakin, and cadherin were
detected in the cell processes (Figure 2A and 2B).
Double-labeling for Cx43 and either desmoplakin or
cadherin showed that these proteins were closely distributed with each
other in the cell process, and the signal for Cx43 was weaker than that
of desmoplakin and cadherin (Figure 2C). Small plaques of all 3
junctional proteins were abundant and closely associated on lateral
surfaces between borderline and/or vicinity cardiomyocytes
(Figure 2D). The number of these lateral plaques gradually
decreased with distance from the infarct. The laminin sheath became
obscure in the infarct (data not shown), and signal for
ß1-integrin was weak at stumps. Double-labeling
for ß1-integrin and other junctional proteins
revealed that ß1-integrin adjoined the
junctional proteins (Figure 2E).
|
On days 8 and 15 postligation, borderline cardiomyocytes
displayed elongated and intertwined cell processes (Figure 3), portraying clear striations even near
the tip. Serial confocal imaging demonstrated that
immunofluorescent spots of Cx43 (Figure 3I through 3L),
desmoplakin (Figure 3A through 3F), and cadherin were
present between the cell processes originating not only from
neighboring cardiomyocytes but also from the same
cardiomyocyte. The expression of Cx43 was comparable with
those of desmoplakin and cadherin at stumps and at cell borders of
vicinity cardiomyocytes. Localization of the 3 proteins on
lateral surfaces was still observed between borderline and/or vicinity
cardiomyocytes (Figure 3G and 3H).
ß1-Integrin was expressed on the surface of
cell processes.
|
During days 30 to 90 postligation, the number of cell processes at
stumps gradually decreased and stumps tapered off. The expression of
Cx43, desmoplakin, and cadherin was attenuated (Figure 4A). In contrast, the expression of
ß1-integrin increased, especially at the tip of
cell processes (Figure 4B).
|
Morphometry
Figure 5 shows that desmoplakin and
cadherin underwent similar changes at all time points. Concerning
vicinity cardiomyocytes, the 3 junctional proteins showed
similar changes, although the amounts were reduced to 
45% to 60%
of those of sham-operated hearts by 48 hours. The protein expression
recovered to levels similar to those of sham on days 8 and 15 and
decreased on day 60. Concerning the stump, the increase in Cx43 after
myocardial infarction was significantly delayed compared with
desmoplakin and cadherin on day 4. The expression of the 3 junctional
proteins increased to levels similar to those of vicinity
cardiomyocytes on days 8 and 15. Furthermore, expression of
the 3 proteins at stumps and between vicinity
cardiomyocytes decreased on day 60. The time-dependent
increase in ß1-integrin at the stump was
confirmed by morphometry, and the expression of
ß1-integrin gradually approached that of
papillary MTJ.
|
Electron Microscopy
In sham-operated left ventricle, typical intercalated disks
existed between cardiomyocytes (data not shown). At 48
hours postligation (Figure 6A), no
apparent gap junctional structure was observed between borderline
cardiomyocytes and necrotic cardiomyocytes with
few remaining myofibrils and cell organelles, although desmosomes and
adherens junctions persisted. On day 3 postligation (Figure 6B),
cell processes were formed at the stumps, and desmosomes, adherens
junctions, and gap junctions were detected between the processes.
Basement membranes were occasionally seen around the cell processes. On
day 4 postligation (Figure 6C), the stump consisted of multiple
small, complex cell processes. Desmosomes and adherens junctions were
present between these cell processes, even near the tip. A few
subsarcolemmal densities existed at the tip of cell processes
surrounded by basement membranes and collagen fibers. On days 8 and 15
postligation (Figure 6D through 6F), intercalated disk–like
junctional complexes containing gap junctions, desmosomes, and adherens
junctions existed in a side-by-side and an end-to-end manner between
elongated cell processes, which had originated from a single
cardiomyocyte. The surfaces of cell processes were
surrounded by basement membranes, and subsarcolemmal densities were
abundantly present at the tip of cell processes. A few contacts
between fibroblasts and cardiomyocytes were observed, but
no apparent gap junctions, desmosomes, and adherens junctions were
recognizable between them (data not shown). On day 60 postligation
(Figure 6G), well-developed subsarcolemmal densities were
detected at the tip of cell processes, distributed in a pattern similar
to that of MTJ of papillary muscle. However, intercalated
disk–like structures were barely detected near the tip. We found no
significant differences in the localization of gap junctions,
desmosomes, adherens junctions and subsarcolemmal densities between
non-arrested and arrested hearts after myocardial infarction (eg,
compare Figure 6D with Figure 6E).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We have shown here that remodeling of gap junctions after myocardial infarction1 2 3 4 5 6 9 20 21 is closely related to changes in desmosomes and adherens junctions and that remodeling of the intercalated disk region at the myocardial interface with areas of scar tissue is associated with acquisition of laminin and ß1-integrin.
We revealed that abnormal localization of gap junctions on the lateral surface between borderline and/or vicinity cardiomyocytes after myocardial infarction often corresponded to that of desmosomes and adherens junctions, consistent with ultrastructural results in infarct zone cardiomyocytes previously reported.2 Our present results showing that abnormal distribution of cell junctions occurred at both borderline cardiomyocytes (in contact with scar tissues) and vicinity cardiomyocytes (not in contact with scar tissues), suggest that direct contact with the scar tissue is not essential to cause the abnormality, but rather, indirect effects such as ischemia may cause the abnormality. The impact of chronic ischemia on the expression of the junctional proteins was also indicated by our data that show that signals for Cx43, desmoplakin, and cadherin decreased on day 60.
The association of gap junctions with adherens junctions may be attributed to regulation of gap junctions by cadherins, a mechanism reported not only in epithelial cells22 23 24 but also in cardiomyocytes.25 26 In addition, we presume that differences in vulnerability to ischemia exist between gap junctions and cell adhesion junctions, because gap junctions attenuate more rapidly than desmosomes and adherens junctions at the early phase. One example of the divergence among the 3 junctions has been reported during postnatal differentiation of ventricular myocardium.7 8 The vulnerability of gap junctions may be attributed to the very rapid turnover of connexins19 and to the lack of their interaction with the cytoskeleton (desmin and actin) to which desmosomes and adherens junctions are bound.
Although the presence of intracellular junctions has previously been reported in cardiomyocytes in human and canine diseased hearts by electron microscopy,27 it is difficult to convincingly demonstrate intracellular junctions in ultrathin sections of heart tissues. Our serial confocal imaging clearly demonstrated that contacts were formed between cell processes from neighboring cardiomyocytes (intercellular) but also from the same cardiomyocyte (intracellular). Cx43, desmoplakin, and cadherin were present between them. By electron microscopy, we frequently encountered junctional complexes containing gap junctions, desmosomes, and adherens junctions between intricately intertwined cell processes of the same cell, whereas annular gap junctions28 in the cytoplasm were rarely observed.
The expression of ß1-integrin and the extent of subsarcolemmal densities by electron microscopy corresponded well with the formation of multiple elongated cell processes at stumps and subsequent anchoring of cardiomyocytes to scar tissues. The cardiomyocyte attachment to scar tissues resembles papillary MTJs with respect to the amounts of integrins and subsarcolemmal densities.29
Figure 7 summarizes the remodeling
process of cell-cell and cell-ECM interactions at the stump during
myocardial infarction. At early phase postligation (48 hours),
borderline cardiomyocytes facing the infarct lose
neighboring cells and form blunt-ended stumps while maintaining some
desmosomes, and adherens junctions lose gap junctions. By day 3,
integrins such as ß1-integrin cluster at stumps
where basement membranes are partially formed. Actin filaments connect
to integrins via adaptor proteins,30 developing cell-ECM
attachment structures identical to focal adhesions in cultured
cells.31 By this attachment, the contractile force of
remaining cardiomyocytes foster cell process formation,
increasing the surface area for anchoring of borderline
cardiomyocytes to ECM. The formation of intracellular
junctions (desmosomes and adherens junctions) is initiated between cell
processes, offering anchoring sites for cytoskeleton to possibly help
maintain the cell shape. After day 3, the presence of desmosomes and
adherens junctions provide favorable conditions for the establishment
of gap junctions between cell processes,22 23 24 25 26 forming
intracellular junctional complexes similar to those of typical
intercalated disks. In the chronic phase (days 60 to 90), integrin-ECM
couplings at the tip of cell processes and collagen accumulation around
the process increase as wound healing proceeded.32 33
Upregulation of integrin expression provides binding sites for actin
filaments, possibly interfering with the binding of actin filaments to
intracellular adherens junctions. Cell processes fuse mutually, and the
intercalated disk–like structures decrease. The
cardiomyocyte attachment to the scar tissue gradually
transforms to papillary MTJ–like structures. However, the mechanical
strength of the attachment on day 90 is still lower than that of MTJ,
and it might be one of the causes of the ventricular
aneurysm.
|
We can assume that the remodeling of cell-cell and cell-ECM interactions described above has important implications for cardiac function. During the early phase of myocardial infarction, impaired intercellular conduction caused by a drastic decrease in gap junctions can delay conduction in specific areas of the heart with resultant re-entry and re-excitation, which causes arrhythmia. In addition to arrhythmia, changes in the desmosomes and adherens junctions may influence transmission of the traction to eventually attenuate contractility. During the healing phase, the disturbed pattern of cell junctions, including gap junctions localized to the lateral surfaces of cardiomyocytes, may cause abnormal conduction in the healing infarct border-zone myocardium, as previously indicated.6 The functional significance of the intracellular gap junctions is unclear; this may contribute to arrhythmias such as aberrant distribution of gap junctions on the lateral surfaces, or, alternatively, they function as antiarrhythmic structures (canceling out harmful electrical impulses by providing a pathway for the collision of impulses). Intracellular adhesion junctions may coordinate the cytoskeleton in forming attachments of cardiomyocytes to scar tissues in concert with integrins. Alternatively, given that mutations in cytoskeletal protein genes, such as dystrophin and metavinculin, have been found in inherited dilated cardiomyopathy,34 irregular distribution of intracellular junctions may contribute to a disruption of the cytoskeleton and onset of dilated myopathy.
Further investigations are needed to elucidate molecular mechanisms for the remodeling of cell-cell and cell-ECM interaction during myocardial infarction, which could lead to treatment and/or prevention of complications after myocardial infarction.
|
Acknowledgments |
|---|
This work was supported by a Grant-in-Aid for Scientific Research from The Ministry of Education, Science, Sports and Culture of Japan. We thank Dr Hideo Yagita for donating the antibodies against mouse ß1-integrin. We are grateful to Dr Nicholas J. Severs (The National Heart and Lung Institute, U.K.) for his advice on English usage.
Received September 2, 1999; accepted September 14, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Severs NJ. Cardiac muscle cell interaction: from microanatomy to the molecular make-up of the gap junction. Histol Histopathol. 1995;10:481–501.[Medline] [Order article via Infotrieve]
2. Smith JH, Green CR, Peters NS, Rothery S, Severs NJ. Altered patterns of gap junction distribution in ischemic heart disease. Am J Pathol. 1991;139:801–821.[Abstract]
3. Green CR, Severs NJ. Distribution and role of gap junctions in normal myocardium and human ischaemic heart disease. Histochemistry. 1993;99:105–120.[Medline] [Order article via Infotrieve]
4. Severs NJ. Cardiovascular disease. Novartis Found Symp.. 1999;219:188–206.[Medline] [Order article via Infotrieve]
5. Matsushita T, Takamatsu T. Ischaemia-induced temporal expression of Cx43 in rat heart. Virchows Archiv. 1997;431:453–458.[Medline] [Order article via Infotrieve]
6.
Peters NS, Coromilas J, Severs NJ, Wit AL. Distributed
connexin43 gap junction distribution correlates with the location of
reentrant circuits in the epicardial border zone of healing canine
infarcts that cause ventricular tachycardia.
Circulation. 1997;95:988–996.
7.
Peters NS, Severs NJ, Rothery SM, Lincoln C, Yacoub
MH, Green CR. Spatiotemporal relation between gap junctions and fascia
adherens junctions during postnatal development of human
ventricular myocardium. Circulation. 1994;90:713–725.
8.
Angst BD, Khan LUR, Severs NJ, Whitely K, Rothery S,
Thompson RP, Magee AI, Gourdie RG. Dissociated spatial patterning of
gap junctions and cell adhesion junctions during postnatal
differentiation of ventricular myocardium.
Circ Res. 1997;80:88–94.
9. Luke RA, Saffitz JE. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest. 1991;87:1594–1602.
10. Borg TK, Ranson WF, Moshlehy FA, Caulfield JB. Structural basis of ventricular stiffness. Lab Invest. 1981;44:49–54.[Medline] [Order article via Infotrieve]
11. Robinson TF, Factor SM, Capasso JM, Whittenberg BA, Blumenfield OO, Seifter S. Morphology, composition, and function of struts between cardiac myocytes of rat and hamster. Cell Tissue Res. 1987;249:247–255.[Medline] [Order article via Infotrieve]
12. Vracko R, Thorning D, Frederickson RG, Cunningham D. Myocyte reactions at the borders of injured and healing rat myocardium. Lab Invest. 1988;59:104–114.[Medline] [Order article via Infotrieve]
13. Vracko R, Thorning D, Frederickson RG. Connective tissue cells in healing rat myocardium: a study of cell reactions in rhythmically contracting environment. Am J Pathol. 1989;134:993–1006.[Abstract]
14.
Jalil JE, Doering CW, Janicki JS, Pick R, Shroff SG,
Weber KT. Fibrillar collagen and myocardial stiffness in the intact
hypertrophied rat left ventricle. Circ Res. 1989;64:1041–1050.
15.
Terracio L, Rubin K, Gullberg D, Balog E, Carver W,
Jyring R, Borg TK. Expression of collagen binding integrins during
cardiac development and hypertrophy. Circ Res. 1991;68:734–744.
16.
Noto K, Kato K, Okumura K, Yagita H.
Identification and functional characterization of mouse CD29 with a
mAb. Int Immunol. 1995;7:835–842.
17.
Kaprielian RR, Gunning M, Dupont E, Sheppard MN,
Rothery SM, Underwood R, Pennell DJ, Fox K, Pepper J, Poole-Wilson PA,
Severs NJ. Downregulation of immunodetectable connexin43 and decreased
gap junction size in the pathogenesis of chronic hibernation in the
human left ventricle. Circulation. 1998;97:651–660.
18. Weibel ER. Practical methods for biological morphometry. In: Stereological Methods. Vol 1. London, UK: Academic Press; 1979:1–415.
19.
Beardslee MA, Laing JG, Beyer EC, Saffitz JE. Rapid
turnover of connexin43 in the adult rat heart. Circ Res. 1998;83:629–635.
20.
Hoyt RH, Cohen ML, Corr PB, Saffitz JE. Alterations of
intercellular junctions induced by hypoxia in canine
myocardium. Am J Physiol. 1990;258:H1439–H1448.
21.
Peters NS, Green CR, Poole-Wilson PA, Severs NJ.
Reduced content of connexin43 gap junctions in ventricular
myocardium from hypertrophied and ischemic human
hearts. Circulation. 1993;88:864–875.
22.
Musil LS, Cunningham BA, Edelman GM, Goodenough DA.
Differential phosphorylation of the gap junction
protein connexin43 in junctional communication-competent and -deficient
cell lines. J Cell Biol. 1990;111:2077–2088.
23.
Jongen WMF, Fitzgerald DJ, Asamoto M, Piccoli C, Slaga
TJ, Gros D, Takeichi M, Yamasaki H. Regulation of connexin43-mediated
gap junctional intercellular communication by Ca2+ in mouse epidermal
cells is controlled by E-cadherin. J Cell Biol. 1991;114:545–555.
24. Fujimoto K, Nagafuchi A, Tsukita S, Kuraoka A, Ohokuma A, Shibata Y. Dynamics of connexins, E-cadherin and alpha-catenin on cell membranes during gap junction formation. J Cell Sci. 1997;110:311–322.[Abstract]
25. Hertig CM, Eppenberger-Eberhardt M, Koch S, Eppenberger HM. N-Cadherin in adult rat cardiomyocytes in culture, I: functional role of N-cadherin and impairment of cell-cell contact by a truncated N-cadherin mutant. J Cell Sci. 1996;109:1–10.[Abstract]
26. Nakagawa S, Takeichi M. N-Cadherin is crucial for heart formation in the chick embryo. Dev Growth Differ. 1997;39:451–455.[Medline] [Order article via Infotrieve]
27. Buja LM, Ferrans VJ, Maron BJ. Intracytoplasmic junctions in cardiac muscle cells. Am J Pathol. 1974;74:613–648.[Medline] [Order article via Infotrieve]
28.
Severs NJ, Shovel KS, Slade AM, Powell T, Twist VW,
Green CR. Fate of gap junctions in isolated adult mammalian
cardiomyocytes. Circ Res. 1989;65:22–42.
29. Tidball JG, Andolina KL. Structure and protein composition of sites of papillary muscle attachment to chordae tendineae in avian hearts. Cell Tissue Res. 1992;270:527–533.[Medline] [Order article via Infotrieve]
30. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69:11–25.[Medline] [Order article via Infotrieve]
31.
Sharp WW, Simpson DG, Borg TK, Samarel AM, Terracio L.
Mechanical forces regulate focal adhesion and costamere assembly in
cardiac myocytes. Am J Physiol. 1997;273:H546–H556.
32.
Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM,
Bashey RI. Collagen remodeling of the pressure-overloaded,
hypertrophied nonhuman primate myocardium. Circ
Res. 1988;62:757–767.
33. Cleutjens JPM, Verluyten MJA, Smits JFM, Daemen MJAP. Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol. 1995;147:325–338.[Abstract]
34. Towbin JA. The role of cytoskeletal proteins in cardiomyopathies. Curr Opin Cell Biol. 1998;10:131–139.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  E. I. Rossman, K. Liu, G. A. Morgan, R. E. Swillo, J. A. Krueger, S. J. Gardell, J. Butera, M. Gruver, J. Kantrowitz, H. S. Feldman, et al. The Gap Junction Modifier, GAP-134 [(2S,4R)-1-(2-Aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic Acid], Improves Conduction and Reduces Atrial Fibrillation/Flutter in the Canine Sterile Pericarditis Model J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 1127 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Hund, P. J. Wright, W. Dun, J. S. Snyder, P. A. Boyden, and P. J. Mohler Regulation of the ankyrin-B-based targeting pathway following myocardial infarction Cardiovasc Res, March 1, 2009; 81(4): 742 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kontogeorgis, X. Li, E. Y. Kang, J. E. Feig, M. Ponzio, G. Kang, R. A. Kaba, A. L. Wit, E. A. Fisher, G. E. Morley, et al. Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1905 - H1916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Severs, A. F. Bruce, E. Dupont, and S. Rothery Remodelling of gap junctions and connexin expression in diseased myocardium Cardiovasc Res, October 1, 2008; 80(1): 9 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Pedrotty, R. Y. Klinger, N. Badie, S. Hinds, A. Kardashian, and N. Bursac Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H390 - H400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakagami, H. Tanaka, P. Dai, S.-F. Lin, T. Tanabe, H. Mani, K. Fujiwara, H. Matsubara, and T. Takamatsu Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers Cardiovasc Res, July 1, 2008; 79(1): 70 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kurebayashi, H. Nishizawa, Y. Nakazato, H. Kurihara, S. Matsushita, H. Daida, and Y. Ogawa Aberrant cell-to-cell coupling in Ca2+-overloaded guinea pig ventricular muscles Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1419 - C1429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Zemljic-Harpf, J. C. Miller, S. A. Henderson, A. T. Wright, A. M. Manso, L. Elsherif, N. D. Dalton, A. K. Thor, G. A. Perkins, A. D. McCulloch, et al. Cardiac-Myocyte-Specific Excision of the Vinculin Gene Disrupts Cellular Junctions, Causing Sudden Death or Dilated Cardiomyopathy Mol. Cell. Biol., November 1, 2007; 27(21): 7522 - 7537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K Parker and D. E Ingber Extracellular matrix, mechanotransduction and structural hierarchies in heart tissue engineering Phil Trans R Soc B, August 29, 2007; 362(1484): 1267 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. E. Tansey, K. F. Kwaku, P. E. Hammer, D. B. Cowan, M. Federman, S. Levitsky, and J. D. McCully Reduction and redistribution of gap and adherens junction proteins after ischemia and reperfusion. Ann. Thorac. Surg., October 1, 2006; 82(4): 1472 - 1479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rucker-Martin, P. Milliez, S. Tan, X. Decrouy, M. Recouvreur, R. Vranckx, C. Delcayre, J.-F. Renaud, I. Dunia, D. Segretain, et al. Chronic hemodynamic overload of the atria is an important factor for gap junction remodeling in human and rat hearts Cardiovasc Res, October 1, 2006; 72(1): 69 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Lindsey, G. P. Escobar, R. Mukherjee, D. K. Goshorn, N. J. Sheats, J. A. Bruce, I. M. Mains, J. K. Hendrick, K. W. Hewett, R. G. Gourdie, et al. Matrix Metalloproteinase-7 Affects Connexin-43 Levels, Electrical Conduction, and Survival After Myocardial Infarction Circulation, June 27, 2006; 113(25): 2919 - 2928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, V. V. Patel, and G. L. Radice Dysregulation of cell adhesion proteins and cardiac arrhythmogenesis. Clin. Med. Res., March 1, 2006; 4(1): 42 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, V. V. Patel, I. Kostetskii, Y. Xiong, A. F. Chu, J. T. Jacobson, C. Yu, G. E. Morley, J. D. Molkentin, and G. L. Radice Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and Arrhythmogenesis Circ. Res., September 2, 2005; 97(5): 474 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kostetskii, J. Li, Y. Xiong, R. Zhou, V. A. Ferrari, V. V. Patel, J. D. Molkentin, and G. L. Radice Induced Deletion of the N-Cadherin Gene in the Heart Leads to Dissolution of the Intercalated Disc Structure Circ. Res., February 18, 2005; 96(3): 346 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schuh, S. Breuer, R. Al Dashti, N. Sulemanjee, P. Hanrath, C. Weber, B. F. Uretsky, and E. R. Schwarz Administration of Vascular Endothelial Growth Factor Adjunctive to Fetal Cardiomyocyte Transplantation and Improvement of Cardiac Function in the Rat Model Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2005; 10(1): 55 - 66. [Abstract] [PDF]
|
|
|
|
|
|
S. B. Danik, F. Liu, J. Zhang, H. J. Suk, G. E. Morley, G. I. Fishman, and D. E. Gutstein Modulation of Cardiac Gap Junction Expression and Arrhythmic Susceptibility Circ. Res., November 12, 2004; 95(10): 1035 - 1041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Severs, S. R. Coppen, E. Dupont, H.-I Yeh, Y.-S. Ko, and T. Matsushita Gap junction alterations in human cardiac disease Cardiovasc Res, May 1, 2004; 62(2): 368 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kostin, S. Dammer, S. Hein, W. P Klovekorn, E. P Bauer, and J. Schaper Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis Cardiovasc Res, May 1, 2004; 62(2): 426 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Heng, H. K. Haider, E. K.-W. Sim, T. Cao, and S. C. Ng Strategies for directing the differentiation of stem cells into the cardiomyogenic lineage in vitro Cardiovasc Res, April 1, 2004; 62(1): 34 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Duffy, A. W. Ashton, P. O'Donnell, W. Coombs, S. M. Taffet, M. Delmar, and D. C. Spray Regulation of Connexin43 Protein Complexes by Intracellular Acidification Circ. Res., February 6, 2004; 94(2): 215 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-A. Yao, W. Hussain, P. Patel, N. S. Peters, P. A. Boyden, and A. L. Wit Remodeling of Gap Junctional Channel Function in Epicardial Border Zone of Healing Canine Infarcts Circ. Res., March 7, 2003; 92(4): 437 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Gutstein, F.-y. Liu, M. B. Meyers, A. Choo, and G. I. Fishman The organization of adherens junctions and desmosomes at the cardiac intercalated disc is independent of gap junctions J. Cell Sci., March 1, 2003; 116(5): 875 - 885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. van den Eijnde, M. J. B. van den Hoff, C. P. M. Reutelingsperger, W. L. van Heerde, M. E. R. Henfling, C. Vermeij-Keers, B. Schutte, M. Borgers, and F. C. S. Ramaekers Transient expression of phosphatidylserine at cell-cell contact areas is required for myotube formation J. Cell Sci., March 12, 2002; 114(20): 3631 - 3642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Gutstein, G. E. Morley, D. Vaidya, F. Liu, F. L. Chen, H. Stuhlmann, and G. I. Fishman Heterogeneous Expression of Gap Junction Channels in the Heart Leads to Conduction Defects and Ventricular Dysfunction Circulation, September 4, 2001; 104(10): 1194 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A.B. van Veen, H. V.M. van Rijen, and T. Opthof Cardiac gap junction channels: modulation of expression and channel properties Cardiovasc Res, August 1, 2001; 51(2): 217 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Ross and T. K. Borg Integrins and the Myocardium Circ. Res., June 8, 2001; 88(11): 1112 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohara, K. Ohara, J.-M. Cao, M.-H. Lee, M. C. Fishbein, W. J. Mandel, P.-S. Chen, and H. S. Karagueuzian Increased Wave Break During Ventricular Fibrillation in the Epicardial Border Zone of Hearts With Healed Myocardial Infarction Circulation, March 13, 2001; 103(10): 1465 - 1472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Gutstein, G. E. Morley, H. Tamaddon, D. Vaidya, M. D. Schneider, J. Chen, K. R. Chien, H. Stuhlmann, and G. I. Fishman Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 Circ. Res., February 16, 2001; 88(3): 333 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Jongsma and R. Wilders Gap Junctions in Cardiovascular Disease Circ. Res., June 23, 2000; 86(12): 1193 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Reinecke, G. H. MacDonald, S. D. Hauschka, and C. E. Murry Electromechanical Coupling between Skeletal and Cardiac Muscle: Implications for Infarct Repair J. Cell Biol., May 1, 2000; 149(3): 731 - 740. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||