Remodeling of Cell-Cell and Cell–Extracellular Matrix Interactions at the Border Zone of Rat Myocardial Infarcts

Abstract

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 (␤ 1 -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. ␤ 1 -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 ␤ 1 -integrin. (Circ Res. 1999;85:1046-1055.)

Structural remodelling of cardiomyocytes in the border zone of infarcted rabbit heart

“…Such regions of viable myocardial cells have also been described for dog heart [18]. The irregular protrusions containing non-structured myofilaments found in our material resemble the CM protrusions described to end in the infarct scar tissue of the rat myocardium [2,19]. Ultrastructurally, the vacuoles were characterized by a basal lamina closely apposed to its surrounding membrane, and by pinocytotic vesicles at their cytoplasmic side.…”

“…5 consecutive slices (I to V) were made of the rabbit heart immediately after perfusion fixation. Several samples were taken from the border zone of infarcted myocardium (1), from the adjacent non-infarcted region (2) and from the remote zone of the left ventricle (3) Localization of hibernating cardiomyocytes…”

“…At the border zone of infarcted myocardium, viable cardiomyocytes (CM's) undergo drastic reorganization of cellcell and cell-extracellular matrix interactions. They lose cell-cell connections because of the death of neighbouring cardiomyocytes and subsequent anchoring to scar tissue [2]. Furthermore, it has been shown that the border zone of infarcted myocardium in larger animals such as dog and sheep may comprise a considerable number of dedifferentiated CM's, which are phenotypically similar to those seen in chronic hibernation [3][4][5].…”

Dysregulation of Cell Adhesion Proteins and Cardiac Arrhythmogenesis

“…[18][19][20] Disturbances in the distribution of gap junctions and reduced levels of Cx43 occur not only in association with established infarct scar tissue in the human heart, but have been shown in experimental animals to be initiated rapidly after ventricular ischemia and infarction. 4,21,22 Alterations in connexin expression and spatial remodeling of gap junctions in regions bordering healing infarcts have been implicated in the development of slow, heterogeneous conduction and conduction block critical in reentrant arrhythmogenesis. 22 More widespread spectacular disordered arrangements of ventricular Cx43 gap junctions are an inevitable consequence of the haphazard myocyte organization characteristic of human hypertrophic cardiomyopathy, the most common cause of SCD due to arrhythmia.…”

“…Aberrant cell-cell coupling through junctional complexes is observed in many of the major forms of human heart disease, as well as in experimental animal heart disease, which is associated with an increased risk of arrhythmias and SCD. [1][2][3][4][5] However, the molecular mechanism underlying cellular uncoupling in the heart with the subsequent development of cardiac electrical disorders and arrhythmogenesis is still poorly understood.…”