The Journal of Experimental Medicine
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doi:10.1084/jem.20081244
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© Schellings et al.
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ARTICLE

 Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction

Mark W.M. Schellings1, Davy Vanhoutte4,6, Melissa Swinnen1, Jack P. Cleutjens2, Jacques Debets3, Rick E.W. van Leeuwen1, Jan d'Hooge5, Frans Van de Werf6, Peter Carmeliet4,7, Yigal M. Pinto1, E. Helene Sage8, and Stephane Heymans1

1 Center for Heart Failure Research, 2 Department of Pathology, and 3 Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, 6229 HX Maastricht, Netherlands
4 Vesalius Research Center (VRC) and 5 Department of Cardiovascular Diseases, K.U. Leuven, 3000 Leuven, Belgium
6 Department of Cardiology, University Hospital of Leuven, B-3000 Leuven, Belgium
7 Vesalius Research Center (VRC), VIB, 3000 Leuven, Belgium
8 Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101

CORRESPONDENCE Stephane Heymans: s.heymans{at}cardio.unimaas.nl

The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell–matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor β (TGF)–mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-β rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.

Abbreviations used: ECM, extracellular matrix; LV, left ventricle; MI, myocardial infarction; mRNA, messenger RNA; shRNA, short hairpin RNA; SMC, smooth muscle cell.

M.W.M. Schellings and D. Vanhoutte contributed equally to this paper.

© 2009 Schellings et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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