Abstract 15602: Chondroitin Sulphate is a Mediator of the Fibrosis-Inflammation Cycle, a Key Process in Chronic Cardiac Remodelling

• Published in: Circulation (New York, N.Y.) Vol. 138; no. Suppl_1 Suppl 1; p. A15602
• Main Authors: Zhao, Rongrong, Ackers-Johnson, Matthew, Pan, Bangfen, Ng, Shiling, Li, Peter, Foo, Roger
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 06.11.2018
• ISSN: 0009-7322; 1524-4539

BackgroundOur lab recently reported that chondroitin sulphate proteoglycans (CSPGs) accumulate in heart tissue of end-stage heart failure patients. In mucopolysaccharidosis (MPS) VI, a rare monogenic disease, loss of function mutations in arylsulfatase B leads to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans. MPS VI patients exhibit a myriad of cardiac syndrome from young age. The discovery of CSPG accumulation in non-MPS patients proved it as a generic process involved in heart failure, and a potential novel treatment target. Subsequently in two rodent models of heart failure, we showed modification of the glycosaminoglycan chains of the CSPGs alleviated inflammation and fibrosis in heart tissue, and prevented cardiac function deterioration.Hypothesis and ResultsWe hypothesized that CSPGs played a role in prolonged inflammation and fibrosis in the chronic cardiac remodeling process. In an in vitro assay, primary human cardiac fibroblasts (hCF) transiently stimulated with inflammatory cytokines produced and released CSPGs into media for a prolonged period of 5 days post treatment. The CSPG-rich fibroblast conditioned media in turn induced IL-1b over expression in macrophages, suggesting an fibrosis-inflammation cycle mediated by CSPGs. Protein composition of the pCF conditioned media was identified with mass spectrometry, and the macrophage transcriptome was profiled with RNA-seq. Specific knock down of the genes involved in proteoglycan production proved CS, rather than core proteins or other GAGs, to be the inflammatory moiety in the pCF conditioned media. Blocking CS with an antibody achieved dose-dependent elimination of pCF-induced macrophage inflammatory responses. Reducing CS production in vivo in a chronic heart failure model resulted in reduced fibrosis formation.ConclusionTransient pathological cytokine stimulation on cardiac fibroblasts results in prolonged CSPG release, which in turn activated macrophage inflammatory cytokine release, forming a malignant cycle that continuously stimulates fibrosis and inflammation, driving chronicle cardiac remodeling.