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

Abstract

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.

Role of the Heparan Sulfate Proteoglycan Syndecan-1 (CD138) in Delayed-Type Hypersensitivity

“…This finding is in line with our previously stated hypothesis that Sdc-1 may modulate vascular permeability via its interaction with kininogens or CAP37 (7) and with an increase in paracellular protein leakage in Sdc-1 KO vs WT mice in a mouse model of protein-losing enteropathy (39). Increased leukocyte recruitment in the absence of Sdc-1 was consistently observed in different contexts of inflammation and repair, including allergic lung inflammation (24), anti-GBM nephritis (25), myocardial infarction (22), and upon TNF-␣-stimulation in vivo (20). We are now providing further mechanistic clues elucidating the role of Sdc-1 in leukocyte recruitment: It has previously been shown that soluble heparin, an extensively sulfated and epimerized form of heparan sulfate, can bind to the leukocyte integrin Mac-1 on stimulated monocytes and granulocytes and is capable of inhibiting binding of ICAM-1 to Mac-1 (40).…”

“…Of note, 48 and 72 h after DTH elicitation, Sdc-1 expression was significantly reduced by 60 -70% compared with unchallenged controls. Similar to our previous findings in a myocardial infarction model (22), no differential expression of the other three members of the Sdc family was seen between Sdc-1 KO and WT mice (data not shown). Sdc-1 modulates the activity of a variety of proteins relevant to inflammation via interactions with its heparan sulfate chains (7)(8)(9), which are capable of forming specific ligand binding sites depending on posttranslational modifications such as epimerization and N-and O-sulfation (10,13).…”

“…Using KO and transgenic mouse models, we and others could recently demonstrate a role for Sdc-1 in regulating inflammation in a variety of disease models: Sdc-1 KO mice show increased adhesion of leukocytes to retinal blood vessels under unstimulated conditions and massively increased leukocyte adhesion and transendothelial diapedesis following TNF-␣ stimulation of mesenteric blood vessels (20). These findings could be replicated in vitro using polymorphonuclear cells (PMNs) purified from the bone marrow of these mice and both murine and human endothelial cells (21,22). In bleomycin-induced lung fibrosis, an essential role for matrilysin-shed Sdc-1 in the generation of a transepithelial gradient of the CXC chemokine KC was demonstrated, leading to survival benefit of Sdc-1 KO mice (23).…”

“…Briefly, 10 g/ml ICAM-1 protein in PBS/1% FCS was coated onto 96-well flatbottom plates (Maxisorp; Nunc). Murine PMNs were prepared from the bone marrow of Sdc-1 KO and WT mice by Histopaque gradient centrifugation exactly as previously described (21,22). PMNs were fluorescently labeled with 2,7-bis-(2-carboxyethyl)-5-carboxyfluorescein acetoxymethyl ester (Invitrogen), washed, and incubated with the ICAM-1-coated plates at a concentration of 3 ϫ 10 5 cells/well in sextuplets for 45 min at 4°C.…”

“…Of note, shed Sdc-1 ectodomains suppressed Th2 cell accumulation in the lung, suggesting an endogenous mechanism by which the airway epithelium limits allergic airway inflammation and obstruction (24). Furthermore, increased leukocyte recruitment in Sdc-1 KO mice was observed in a model of myocardial infarction, concomitant with a differential up-regulation of the chemokine MCP-1/CCL2, exaggerated inflammation, and functionally adverse wound repair (22). Finally, in experimental antiglomerular basement membrane (anti-GBM) nephritis, glomerular leukocyte/macrophage influx was increased in Sdc-1 KO mice during the heterologous phase and influx of CD4 ϩ /CD8 ϩ T cells was higher in the autologous phase, resulting in a more severe glomerular injury (25).…”