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Cardiovascular Research 2000 47(4):645-647; doi:10.1016/S0008-6363(00)00164-4
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Integrins and cell structure: powerful determinants of heart development and heart function

Jürgen Hescheler* and Bernd K. Fleischmann

Zentrum Physiologie und Pathophysiologie der Universität zu Köln, Institut für Neurophysiologie, Robert-Koch-Str. 39, D-50931, Köln, Germany

* Corresponding author. Tel.: +49-221-478-6960; fax: +49-221-478-6965 j.hescheler{at}uni-koeln.de

Received 26 June 2000; accepted 26 June 2000

See article by Maitra et al. [12] (pages 715–725) in this issue.

Integrins comprise a family of cell surface receptors known to attach cells to the extracellular matrix (ECM) and to mediate mechanical as well as chemical signals. Beyond ECM-mediated signalling to the cytosol (outside–in), extracellular binding activities are regulated through integrin-mediated signalling in the opposite direction (inside–out). Because integrins assemble large signalling complexes and activate multiple signalling pathways they are involved in an array of elementary biological functions such as control of cell cycle, proliferation as well as apoptosis [1].

Integrins are heterodimers composed of non-covalently associated {alpha}- and β-subunits. In mammals at least eight β- and 16 {alpha}-subunits combining for 22 different receptors have been identified so far [2]. The β1-subunit composes the largest subfamily of integrins since it can associate with at least ten different {alpha}-subunits [3]. Integrins are widely expressed and dynamically regulated during development [4–6]. Their important role during early organotypic development has been unequivocally demonstrated in knock out models. For instance, deletion of the β1-integrin gene has resulted in early embryonic death during or shortly after implantation. Using a variety of elegant animal and cell models, deletion of the β1-integrin gene was further found to result in severe defects of migration and homing of cells of the hematopoietic system [7], alterations in neuronal development [8,9] and defective vasculo/angiogenesis [10]. Moreover, using β1-integrin deficient embryonic stem cells for the in vitro differentiation of cardiomyocytes, severely disturbed cardiomyogenesis was also observed [11]. The β1-integrin deficient cardiomyocytes displayed defective myofibrillogenesis and no cardiomyocytes with the typical electrical properties (action potentials) of ventricular-, atrial- and nodal-like cells were found.

This issue of Cardiovascular Research contains another example where an important role of integrins in cardiac development is shown. Maitra et al. [12] studied the expression pattern of integrins from the fetal (F17) to the neonatal stage (N2) in primary rat cardiomyocytes. By using RT-PCR they found that at F17 only β1A was present while the isoform β1D appeared at F18, increased at N2 and remained constant thereafter. The {alpha}3-, {alpha}6- and {alpha}7-subunits were extremely low at the fetal stage, whereas after birth {alpha}3- and {alpha}6-subunits transiently increased and at the adult stage only the {alpha}7-subunit persisted. The fact that β1-integrin blocking antibodies arrested the cell cycle at the fetal but not at the neonatal stage of development led the authors to the conclusion that cell attachment via β1-integrins is involved in regulation of cell cycle activity, as suggested earlier for other cell types. The present study fits also well to previous ones on mesodermal development. Obviously ‘structure-dependent signalling cascades’ are present already very early during the mammalian development. It is well known that integrins are involved in intracellular signalling cascades and regulation of tissue specific gene expression (reviewed in Refs. [13,14]). Evidence has been presented that there is a close relationship between regulatory genes involved in mesoderm formation and in cell adhesion such as integrins [15]. For example mice with a deletion of the {alpha}5-integrin gene [16] showed a defect in posterior mesoderm formation very similar to mice carrying mutations in genes coding for brachyury [17,18], for Csk tyrosine kinase [19,20] and for the signalling molecule Wnt-3A [21]. Thus, the altered mesoderm formation upon deletion of {alpha}5- or β1-integrins, points to an important function of these receptors during mesodermal commitment. This notion has been further extended in the present paper of Maitra et al. [12]. The substantial changes in the pattern of integrin expression during cardiac development imply their involvement in this process. How is it mediated? One possibility is, of course, through activating various protein tyrosine kinases, known to be critically involved in cell growth and cell differentiation [1]. Another interesting possibility is, however, the structural patterning mediated by integrins. Maitra et al. [12] could demonstrate by blocking antibodies that the integrins appear causally involved in the modulation of cell cycle. This may depend on the attachment via β1-integrins and correlate also with changes of β1 splice variants and their respective {alpha} isoforms.

Why do these data fascinate? In our view they throw new light on existing concepts of signalling cascades. It is well established that among others several basement membrane proteins, in particular, most of the laminin isoforms, collagen IV and perlecan, bind strongly to integrin receptors, mainly of the β1 chain subfamily [22]. An interaction of basement membrane components via β1-integrins was shown for different signalling pathways such as growth factor-mediated MAPK activity [23,24]. Thus, the role of integrins as anchoring proteins for the cytoskeleton and multiple interaction sites with different intracellular signalling cascades [1] raises the important question whether integrins regulate assembly and function of other membrane receptors, ion channels and downstream signalling molecules as reported for PDZ domains and caveolin.

Here, interesting aspects for future experimental work arise. Up to now the specificity of signalling cascades has been more or less discussed on the basis of selective protein–protein interactions. However, novel data imply a more flexible regime of signalling which is closely related to both signalling molecules such as integrins, and the subcellular microarchitecture with its obvious changes occurring during development or differentiation. Thus, integrins together with cytoskeletal components and/or ECM may form cellular microcompartments which could determine the respective signalling pathways. Examples for microcompartments/microdomains determining the signalling-function relation in cardiomyocytes are known already. For example, recent interest has been directed to the question whether the various signalling components involved in the cAMP-dependent phosphorylation of voltage-dependent calcium channels (VDCC) together with a receptor-dependent modulation of the adenylylcyclase are colocalized in microdomains. The Fischmeister group [25] has demonstrated, using double voltage clamp and double-barrelled microperfusion techniques, that in frog ventricular myocytes VDCC are indeed regulated in a cytoplasmic cAMP compartment positioned in close vicinity to the cell membrane. Moreover, this compartment of cAMP is provided by its tight spatial control through phosphodiesterases preventing diffusion over the length of the cardiomyocyte. Another example are Ca2+ release events called SPARKs. It is assumed that in the T-tubuli of ventricular cardiomyocytes VDCC are in close vicinity to ryanodine release channels of the sarcoplasmic reticulum [26] allowing crosstalk and tight spatial control of the Ca2+-induced Ca2+ release (CICR) mechanism. This creates intracellular gradients of cytosolic Ca2+ concentration which may be important physiological determinants for heart function.

Coming back to the integrins, which likely play an important role during cardiac development, it is tempting to speculate that they are also involved in the regulation of heart function. This is at least suggested by previous work on β1-integrin-deficient embryonic stem cell-derived cardiomyocytes, where no change in the expression and the biophysical characteristics of ion channels, but a clear increase in the rate of spontaneous contractions and arrhythmias were observed [11]. Whether such elementary functions as inotropy and CICR are also altered in integrin-deficient cardiomyocytes requires further research. It is however tempting to speculate that both the perturbed cytoarchitecture and the loss of integrin-mediated signalling underlie the prominent phenotype. Since mutations of cytoskeletal proteins have been found to result in dilated cardiomyopathy [27], further investigation of the role of ‘master molecules’ as integrins may provide novel insight into heart development, regulation of heart function and mechanisms underlying heart disorders.


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