Deletion of alpha 7 integrin gene results in structural heart modifications

Within the integrin family, the alpha7beta1 integrin is the major transmembrane laminin-receptor of skeletal, cardiac and smooth muscle cells. Due to interactions with the actin cytoskeleton, this integrin is essential for structural integrity and mechanical properties of muscle cells, but it is also involved in signal transduction pathways triggered by laminin. Knock out mice have been obtained by generation of null allele of the alpha 7 gene (itga7) in the germline of mice by homologous recombination in embryonic stem cells (1). Absence of integrin alpha 7 chain expression in the skeletal muscle has been reported to correlate with histological changes as for muscular dystrophy and damage of the myotendinous junctions (1,2). Previously, we reported the localization of alpha 7 integrin chain in the heart at the surface of cardiomyocytes with predominance at the myo-tendinous junction between papillary muscles and "chordae tendinae". In the present investigation we examined myo-cardium of 5 K.O. mice at the ultrastructural level. A series of distinct alterations was found to affect myocardium in all animals in different heart areas but at varying degrees. Ultrastructural analysis revealed the presence of cross corrugation at the myocardium fiber surface, following the sarcomeric patterns, being each valley bottom connected with a sarcomeric Z line; often sub-sarcolemmal material connecting longitudinally subsequent Z lines was also detectable. In apical cardiomyocytes of papillary muscle the presence of prominent increase of plasmalemma infolding involved in myo-tendinous junction was observed, as well as abnormal thickening of basal laminae and accumulation of intracytoplasmic material. These dsata suggest that integrin alpha 7 deficiency causes severe alterations in the myocariocyte cytoskeleton associated with a disturbance in cell-extracellular matrix interactions. Moreover, the lateral modifications exhibited by the cardiomyocytes suggest that minor cohesiveness between cells and extracellular matrix should result in less reduction of the heart chambre volume during systole. On the other hand, the increase in the interface between papillary muscles and "chordae tendinae" should represent a compensatory adaptation for the absence of these major adhesive molecules. REFERENCES. (1) U. Mayer et al., Nat Genet, 17: 318-323, 1997. (2) N. Miosge et al., Lab Invest, 79: 1591-1599, 1999.