title: Chemokines regulate small leucine-rich proteoglycans in the extracellular matrix of the pressure-overloaded right ventricle.
abstract: Chemokines have been suggested to play a role during development of left ventricular failure, but little is known about their role during right ventricular (RV) remodeling and dysfunction. We have previously shown that the chemokine (C-X-C motif) ligand 13 (CXCL13) regulates small leucine-rich proteoglycans (SLRPs). We hypothesized that chemokines are upregulated in the pressure-overloaded RV, and that they regulate SLRPs. Mice with RV pressure overload following pulmonary banding (PB) had a significant increase in RV weight and an increase in liver weight after 1 wk. Microarray analysis (Affymetrix) of RV tissue from mice with PB revealed that CXCL10, CXCL6, chemokine (C-X3-C motif) ligand 1 (CX3CL1), chemokine (C-C motif) ligand 5 (CCL5), CXCL16, and CCL2 were the most upregulated chemokines. Stimulation of cardiac fibroblasts with these same chemokines showed that CXCL16 increased the expression of the four SLRPs: decorin, lumican, biglycan, and fibromodulin. CCL5 increased the same SLRPs, except decorin, whereas CX3CL1 increased the expression of decorin and lumican. CXCL16, CX3CL1, and CCL5 were also shown to increase the levels of glycosylated decorin and lumican in the medium after stimulation of fibroblasts. In the pressure-overloaded RV tissue, Western blotting revealed an increase in the total protein level of lumican and a glycosylated form of decorin with a higher molecular weight compared with control mice. Both mice with PB and patients with pulmonary stenosis had significantly increased circulating levels of CXCL16 compared with healthy controls measured by enzyme immunoassay. In conclusion, we have found that chemokines are upregulated in the pressure-overloaded RV and that CXCL16, CX3CL1, and CCL5 regulate expression and posttranslational modifications of SLRPs in cardiac fibroblasts. In the pressure-overloaded RV, protein levels of lumican were increased, and a glycosylated form of decorin with a high molecular weight appeared.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Kirkeveien 166, Oslo, Norway. anne.wahre@medisin.uio.no
authors.forename: Anne
authors.initials: A
authors.lastname: Waehre
authors.forename: Maria
authors.initials: M
authors.lastname: Vistnes
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Ståle
authors.initials: S
authors.lastname: Nygård
authors.forename: Cathrine
authors.initials: C
authors.lastname: Husberg
authors.forename: Ida Gjervold
authors.initials: IG
authors.lastname: Lunde
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.forename: Leif E
authors.initials: LE
authors.lastname: Vinge
authors.forename: Dina
authors.initials: D
authors.lastname: Behmen
authors.forename: Christian
authors.initials: C
authors.lastname: Neukamm
authors.forename: Henrik
authors.initials: H
authors.lastname: Brun
authors.forename: Erik
authors.initials: E
authors.lastname: Thaulow
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
mesh_terms: D000293:Adolescent; D000818:Animals; D016022:Case-Control Studies; D018946:Chemokine CCL5 / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000378:metabolism; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism*; D007223:Infant; D007930:Leucine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011509:Proteoglycans / Q000378:metabolism*; D011666:Pulmonary Valve Stenosis / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000378:metabolism*
chemical_list: C423727:CXCL16 protein, human; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D054428:Chemokine CX3CL1; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D018925:Chemokines; D019743:Chemokines, CXC; C515539:Cx3cl1 protein, mouse; C498926:Cxcl16 protein, mouse; D011509:Proteoglycans; D051116:Receptors, Scavenger; D007930:Leucine