title: Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice.
abstract: Inflammation is central to heart failure progression. Innate immune signaling increases expression of the transmembrane proteoglycan syndecan-4 in cardiac myocytes and fibroblasts, followed by shedding of its ectodomain. Circulating shed syndecan-4 is increased in heart failure patients, however the pathophysiological and molecular consequences associated with syndecan-4 shedding remain poorly understood. Here we used lipopolysaccharide (LPS) challenge to investigate the effects of syndecan-4 shedding in the heart. Wild-type mice (10mg/kg, 9h) and cultured neonatal rat cardiomyocytes and fibroblasts were subjected to LPS challenge. LPS increased cardiac syndecan-4 mRNA without altering full-length protein. Elevated levels of shedding fragments in the myocardium and blood from the heart confirmed syndecan-4 shedding in vivo. A parallel upregulation of ADAMTS1, ADAMTS4 and MMP9 mRNA suggested these shedding enzymes to be involved. Echocardiography revealed reduced ejection fraction, diastolic tissue velocity and prolonged QRS duration in mice unable to shed syndecan-4 (syndecan-4 KO) after LPS challenge. In line with syndecan-4 shedding promoting immune cell recruitment, expression of immune cell markers (CD8, CD11a, F4/80) and adhesion receptors (Icam1, Vcam1) were attenuated in syndecan-4 KO hearts after LPS. Cardiomyocytes and fibroblasts exposed to shed heparan sulfate-substituted syndecan-4 ectodomains showed increased Icam1, Vcam1, TNFα and IL-1β expression and NF-κB-activation, suggesting direct regulation of immune cell recruitment pathways. In cardiac fibroblasts, shed ectodomains regulated expression of extracellular matrix constituents associated with collagen synthesis, cross-linking and turnover. Higher syndecan-4 levels in the coronary sinus vs. the radial artery of open heart surgery patients suggested that syndecan-4 is shed from the human heart. Our data demonstrate that shedding of syndecan-4 ectodomains is part of the cardiac innate immune response, promoting immune cell recruitment, extracellular matrix remodeling and mitigating cardiac dysfunction in response to LPS.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway. Electronic address: m.e.strand@medisin.uio.no.
authors.forename: Mari E
authors.initials: ME
authors.lastname: Strand
authors.affiliation: Bjørknes College, Oslo, Norway.
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Braathen
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Heidi
authors.initials: H
authors.lastname: Kvaløy
authors.affiliation: KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway; Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: Theis
authors.initials: T
authors.lastname: Tønnessen
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway; Department of Genetics, Harvard Medical School, Boston MA, USA.
authors.forename: Ida G
authors.initials: IG
authors.lastname: Lunde
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology; D000071097:ADAMTS1 Protein; D000071121:ADAMTS4 Protein; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006333:Heart Failure / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D013318:Stroke Volume; D053671:Syndecan-4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D008070:Lipopolysaccharides; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D019010:Vascular Cell Adhesion Molecule-1; C036763:monocyte-macrophage differentiation antigen; D018799:Intercellular Adhesion Molecule-1; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C486323:Adamts1 protein, mouse; D011348:Procollagen N-Endopeptidase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse
keywords: Fibrosis; Heart failure; Innate immunity; Proteoglycan; Sepsis