Perlecan is critical for heart stability.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Sasse
Philipp
P
Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Malan
Daniela
D
Fleischmann
Michaela
M
Roell
Wilhelm
W
Gustafsson
Erika
E
Bostani
Toktam
T
Fan
Yun
Y
Kolbe
Thomas
T
Breitbach
Martin
M
Addicks
Klaus
K
Welz
Armin
A
Brem
Gottfried
G
Hescheler
Jürgen
J
Aszodi
Attila
A
Costell
Mercedes
M
Bloch
Wilhelm
W
Fleischmann
Bernd K
BK
D000818:Animals; D001485:Basement Membrane / Q000503:physiopathology; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006321:Heart / Q000196:embryology* / Q000502:physiology*; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D018408:Patch-Clamp Techniques; D016277:Ventricular Function, Left / Q000502:physiology*
D019812:Heparan Sulfate Proteoglycans; C071927:perlecan