Increased expression of syndecan-1 protects against cardiac dilatation and dysfunction after myocardial infarction.
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).


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.
Vanhoutte
Davy
D
Experimental and Molecular Cardiology/CARIM, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
Schellings
Mark W M
MW
Götte
Martin
M
Swinnen
Melissa
M
Herias
Veronica
V
Wild
Martin K
MK
Vestweber
Dietmar
D
Chorianopoulos
Emmanuel
E
Cortés
Víctor
V
Rigotti
Attilio
A
Stepp
Mary-Ann
MA
Van de Werf
Frans
F
Carmeliet
Peter
P
Pinto
Yigal M
YM
Heymans
Stephane
S
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D003094:Collagen / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000502:physiology; D007962:Leukocytes / Q000276:immunology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016296:Mutagenesis; D009203:Myocardial Infarction / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D053668:Syndecan-1 / Q000235:genetics* / Q000502:physiology*; D013599:Systole / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics* / Q000276:immunology
D016207:Cytokines; D012333:RNA, Messenger; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9