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A new target for treating heart failure
At its base, inflammation is simply the immune system's response to injury, when white blood cells flood the site of a wound or infection. Sometimes, however, that immune response can go haywire, and inflammation can be a facet of chronic disease, such as heart disease. In a joint discovery by the National University Health System (NUHS), A*STAR’s Genome Institute of Singapore (GIS) and the National University of Singapore (NUS) Yong Loo Lin School of Medicine, it was revealed that there is another culprit that can be added to the list of inflammation triggers: chondroitin sulfate.
This group of molecules is usually found solely in connective tissues such as cartilage. In the case of the heart, however, this multi-institute team found that chondroitin sulfate collects and causes inflammation in the hearts of individuals with heart failure. Chondroitin sulfate is a polysaccharide, or long chair of sugar molecules, and forms molecular 'nets' outside of cells. The results were published in Circulation, a journal of the American Heart Association, in an article titled "Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling."
As reported in the Circulation paper, “In the monogenic disease mucopolysaccharidosis (MPS) VI, loss of function mutations in arylsulfatase B (ASB) leads to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans (GAGs), manifesting as a myriad of cardiac symptoms.” Mucopolysaccharidoses are metabolic disorders that result from the absence or malfunction of lysosomal enzymes that traditionally degrade GAGs.
“In the rare disease known as Mucopolysaccharidosis (MPS) Type VI, patients have a genetic mutation that leads to systemic chondroitin sulfate accumulation. Because of this, MPS IV patients end up with multi-organ failure, including irregular heartbeats, enlarged heart muscles which may eventually result in heart failure. This evidence gives a very clear link between chondroitin sulfate accumulation and heart diseases,” said Dr Zhao Rongrong from the NUHS’ Cardiovascular Research Institute, co-author of the study.
The team worked with heathy and disease left ventricles from both humans and rats, and all samples underwent histological and immuno-staining methods to determine GAG content. The GAGs were then “extracted and analyzed for quantitative and compositional changes using Alcian Blue assay and liquid chromatography mass spectrometry.” The researchers looked for expression changes in 20 genes related to chondroitin sulfate in three human heart cell types as well as “THP-1 derived macrophages under each of nine in-vitro stimulatory conditions,” according to the paper.
In a pair of rat models “of pathological remodeling induced by transverse aortic constriction (TAC) or isoprenaline infusion,” the team administered recombinant human arylsulfatase B (rhASB) intravenously for seven or five weeks, respectively. rhASB is clinically used as an enzyme replacement therapy to treat patients with MPS VI. Following administration, the paper reports, the scientists measured cardiac function, myocardial fibrosis and inflammation using echocardiography and histology. In addition, “CS-interacting molecules were assessed using surface plasmon resonance and a mechanism of action was verified in vitro.”
What they found was that diseased hearts, even those from individuals who didn't have MPS VI, presented with chondroitin sulfate accumulation. Specifically, the paper reported. “CS GAGs accumulate during cardiac pathological remodeling, and mediate myocardial inflammation and fibrosis.” When treated with rhASB, however, fibrosis and disease progression were effectively treated in the rat models.
“There are more examples now that prove that understanding rare diseases gives us clues for how to treat common conditions,” remarked Associate Professor Roger Foo, Senior Consultant, Department of Cardiology at the National University Heart Centre, Singapore, and lead author of the study. “We have learnt that chondroitin sulfate molecular nets don't only accumulate inside the heart muscle of patients with MPS VI. Heart failure patients without MPS VI also have these molecular nets, which can be targeted with a medicine that is already US FDA-approved. Targeting these molecular nets may bring a fresh new treatment approach for patients with this severe debilitating disease.” Foo is also principal investigator at the NUHS’ Cardiovascular Research Institute and at A*STAR’s GIS.
This is not the only heart-related work out of A*STAR's GIS in the last few months. In the third quarter of 2017, the institute shared news that it had uncovered a new molecule that could potentially be capable of triggering damaged heart cells to heal or regenerate. The research team—consisting of A*STAR's GIS and the NUHS—identified a long non-coding ribonucleic acid that regulates the genes that control heart cells' ability to repair or regenerate themselves. The RNA has been named “Singheart.”