Cardiovascular Research Advance Access originally published online on August 10, 2008
Cardiovascular Research 2008 80(3):435-444; doi:10.1093/cvr/cvn225
Perlecan is critical for heart stability
1 Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany
2 Department of Molecular and Cellular Sport Medicine, German Sport University, Carl-Diem-Weg 6, 50933 Cologne, Germany
3 Department of Agrobiotechnology, IFA-Tulln, Institute of Biotechnology in Animal Production, University of Natural Resources and Applied Life Sciences, Vienna, Vienna, 3430 Tulln, Austria
4 Department of Cardiac Surgery, University of Bonn, 53105 Bonn, Germany
5 Department of Experimental Pathology, University of Lund, 22184 Lund, Sweden
6 Institute of Neurophysiology, University of Cologne, 50931 Cologne, Germany
7 Institute of Anatomy I, University of Cologne, 50931 Cologne, Germany
8 Max Planck Institute for Biochemistry, 82152 Martinsried, Germany
9 Department of Biochemistry and Molecular Biology, University of Valencia, 46100 Burjassot, Spain
* Corresponding authors. Tel: +49 228 6885 200 (B.K.F.)/+49 221 4982 5380 (W.B.); fax: +49 228 6885 201 (B.K.F.)/+49 221 4982 8370 (W.B.). E-mail address: bernd.fleischmann{at}uni-bonn.de (B.K.F.)/w.bloch{at}dshs-koeln.de (W.B.)
Aims: Perlecan is a heparansulfate proteoglycan found in basement membranes, cartilage, and several mesenchymal tissues that form during development, tumour growth, and tissue repair. Loss-of-function mutations in the perlecan gene in mice are associated with embryonic lethality caused primarily by cardiac abnormalities probably due to hemopericards. The aim of the present study was to investigate the mechanism underlying the early embryonic lethality and the pathophysiological relevance of perlecan for heart function.
Methods and results: Perlecan-deficient murine embryonic stem cells were used to investigate the myofibrillar network and the electrophysiological properties of single cardiomyocytes. The mechanical stability of the developing perlecan-deficient mouse hearts was analysed by microinjecting fluorescent-labelled dextran. Maturation and formation of basement membranes and cell–cell contacts were investigated by electron microscopy, immunohistochemistry, and western blotting. Sarcomere formation and cellular functional properties were unaffected in perlecan-deficient cardiomyocytes. However, the intraventricular dye injection experiments revealed mechanical instability of the early embryonic mouse heart muscle wall before embryonic day 10.5 (E10.5). Accordingly, perlecan-null embryonic hearts contained lower amounts of the critical basement membrane components, collagen IV and laminins. Furthermore, basement membranes were absent in perlecan-null cardiomoycytes whereas adherens junctions formed and matured around E9.5. Infarcted hearts from perlecan heterozygous mice displayed reduced heart function when compared with wild-type hearts.
Conclusion: We propose that perlecan plays an important role in maintaining the integrity during cardiac development and is important for heart function in the adult heart after injury.
KEYWORDS Basement membranes; Extracellular matrix; Infarction; Hemopericard; Ventricular function
Time for primary review: 27 days
These authors contributed equally to this work.