Published Online
on January 22, 2007

A more recent version of this article appeared on January 30, 2007

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Submitted on June 8, 2006
Accepted on November 20, 2006

Increased Expression of Syndecan-1 Protects Against Cardiac Dilatation and Dysfunction After Myocardial Infarction

Davy Vanhoutte MS, Mark W.M. Schellings MS, Martin Götte MS, PhD, Melissa Swinnen MS, Veronica Herias PhD, Martin K. Wild PhD, Dietmar Vestweber PhD, Emmanuel Chorianopoulos MD, PhD, Víctor Cortés MS, Attilio Rigotti MD, PhD, Mary-Ann Stepp PhD, Frans Van de Werf MD, PhD, Peter Carmeliet MD, PhD, Yigal M. Pinto MD, PhD, and Stephane Heymans MD, PhD^*

From Experimental and Molecular Cardiology/CARIM, University of Maastricht, Maastricht, the Netherlands (M.W.M.S., M.S., V.H., Y.M.P., S.H.); Molecular and Vascular Biology and Center for Transgene Technology and Gene Therapy, VIB (D. Vanhoutte, E.C., P.C.) and Department of Cardiology (F.V.d.W.), University of Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, Muenster University Hospital, Muenster, Germany (M.G.); Max Planck Institute for Molecular Biomedicine, c/o Institute of Cell Biology, ZMBE, Muenster, Germany (M.K.W., D. Vestweber); Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Marcoleta, Santiago, Chile (V.C., A.R.); and George Washington University Medical Center, Washington, DC (M.-A.S.).

^* To whom correspondence should be addressed. E-mail: s.heymans{at}cardio.unimaas.nl.

Background--The cell-associated proteoglycan syndecan-1 (Synd1) closely regulates inflammation and cell-matrix interactions during wound healing and tumorigenesis. The present study investigated whether Synd1 may also regulate cardiac inflammation, matrix remodeling, and function after myocardial infarction (MI).

Methods and Results--First, we showed increased protein and mRNA expression of Synd1 from 24 hours on, reaching its maximum at 7 days after MI and declining thereafter. Targeted deletion of Synd1 resulted in increased inflammation and accelerated, yet functionally adverse, infarct healing after MI. In concordance, adenoviral gene expression of Synd1 protected against exaggerated inflammation after MI, mainly by reducing transendothelial adhesion and migration of leukocytes, as shown in vitro. Increased inflammation in the absence of Synd1 resulted in increased monocyte chemoattractant protein-1 expression, increased activity of matrix metalloproteinase-2 and -9, and decreased activity of tissue transglutaminase, associated with increased collagen fragmentation and disorganization. Exaggerated inflammation and adverse matrix remodeling in the absence of Synd1 increased cardiac dilatation and impaired systolic function, whereas gene overexpression of Synd1 reduced inflammation and protected against cardiac dilatation and failure.

Conclusions--Increased expression of Synd1 in the infarct protects against exaggerated inflammation and adverse infarct healing, thereby reducing cardiac dilatation and dysfunction after MI in mice.

Key words: gene therapy • heart failure • inflammation • myocardial infarction • remodeling

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