title: The Heparan Sulfate Proteoglycan Glypican-6 Is Upregulated in the Failing Heart, and Regulates Cardiomyocyte Growth through ERK1/2 Signaling.
abstract: Pressure overload is a frequent cause of heart failure. Heart failure affects millions of patients worldwide and is a major cause of morbidity and mortality. Cell surface proteoglycans are emerging as molecular players in cardiac remodeling, and increased knowledge about their regulation and function is needed for improved understanding of cardiac pathogenesis. Here we investigated glypicans (GPC1-6), a family of evolutionary conserved heparan sulfate proteoglycans anchored to the extracellular leaflet of the cell membrane, in experimental and clinical heart failure, and explored the function of glypican-6 in cardiac cells in vitro. In mice subjected to pressure overload by aortic banding (AB), we observed elevated glypican-6 levels during hypertrophic remodeling and dilated, end-stage heart failure. Consistently, glypican-6 mRNA was elevated in left ventricular myocardium from explanted hearts of patients with end-stage, dilated heart failure with reduced ejection fraction. Glypican-6 levels correlated negatively with left ventricular ejection fraction in patients, and positively with lung weight after AB in mice. Glypican-6 mRNA was expressed in both cardiac fibroblasts and cardiomyocytes, and the corresponding protein displayed different sizes in the two cell types due to tissue-specific glycanation. Importantly, adenoviral overexpression of glypican-6 in cultured cardiomyocytes increased protein synthesis and induced mRNA levels of the pro-hypertrophic signature gene ACTA1 and the hypertrophy and heart failure signature genes encoding natriuretic peptides, NPPA and NPPB. Overexpression of GPC6 induced ERK1/2 phosphorylation, and co-treatment with the ERK inhibitor U0126 attenuated the GPC6-induced increase in NPPA, NPPB and protein synthesis. In conclusion, our data suggests that glypican-6 plays a role in clinical and experimental heart failure progression by regulating cardiomyocyte growth through ERK signaling.
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors: Arne O
authors: AO
authors: Melleby
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors: Mari E
authors: ME
authors: Strand
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors: Andreas
authors: A
authors: Romaine
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors: Kate M
authors: KM
authors: Herum
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.|Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway.
authors: Biljana
authors: B
authors: Skrbic
authors: Center for Heart Failure Research, University of Oslo, Oslo, Norway.|Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
authors: Christen P
authors: CP
authors: Dahl
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.|Division of Molecular and Cellular Biology, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors: Ivar
authors: I
authors: Sjaastad
authors: Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway.
authors: Arnt E
authors: AE
authors: Fiane
authors: Division of Molecular and Cellular Biology, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors: Jorge
authors: J
authors: Filmus
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors: Geir
authors: G
authors: Christensen
authors: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors: Ida G
authors: IG
authors: Lunde
mesh_terms: D000818:Animals; D053673:Glypicans / Q000378:metabolism*; D057809:HEK293 Cells; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism*; D041681:NIH 3T3 Cells; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: D053673:Glypicans; C541437:glypican 6 protein, mouse