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Project

Matricellular proteins, thrombospondin-2 and SPARC (osteonectin), protect against heart failure.

Heart failure (HF) affects over 11 million people in the USA and Europe, and is a major cause of hospitalization and mortality. The major causes of HF are haert disease, hypertension and viral infection in the heart. Despite clinical standards, better understanding the pathogenesis of HF is essential to improve diagnosis and treatment strategies. Matricellular proteins, markers of hearts prone to failure. Matricellular proteins (MCPs) are a group of non-structural glycoproteins present in the extracellular matrix, including thrombospondins, SPARC (Secreted protein Acidic and Rich in Cystein or osteonectin), syndecans, periostin and osteoprotegering. They mainly regulate cell-matrix interactions during tissue repair or tumor formation. Unlike structural collagens, MCPs do not contribute directly to structural integrity, but influence cell function by modulating (i) cell-matrix interactions, (ii) integrin-signaling, (iii) growth factors and (iv) matrix metalloproteinase (MMP) activity. Their expression is low to absent in the normal heart, but re-appears at high levels during cardiac stress or injury, which suggests a vital function of these proteins in wound healing and cardiac remodeling. We were the first to demonstrate that syndecan-1 and thrombospondin-2 (TSP2) are crucial for the heart to cope with ischemia or increased loading, whereas others revealed a cardio-protective effect of osteopontin against hypertensive and ischemic heart disease. Absence of TSP2 resulted in cardiac rupture or pronounced HF in response to mild cardiac loading, associated with increased MMP-2 and -9 activity, dilatation and dysfunction. We also found exciting new data that TSP2-deficient mice spontaneously develop dilated cardiomyopathy (DCM; unpublished). We observed a 40% increase in mortality in TSP2-deficient mice compared to wild type mice progressing from 33 to 60 weeks after birth. Detailed histopathological and functional analysis revealed that this age-related-DCM is associated with (i) increased cardiomyocyte aging, suffering and necrosis, (ii) cardiac fibrosis, dilatation and depressed systolic function, whereas no differences are seen at younger age. TSP2-deficient mice therefore provide a unique model of aging-related DCM. Many questions regarding the biological role of MCPs in the progression to HF still remain. Intriguingly, both TSP2 and SPARC interact with beta1-integrin and act as co-factors for TGFbeta1-signaling2. Both pathways are involved in (i) regulating the function of inflammatory cells (including T-cells, neutrophils, monocytes), (ii) regulation of MMP expression and activity, and (iii) ECM remodeling. In addition, beta1-integrin-signaling is crucial for myocyte survival, physiological hypertrophy and prevention of cardiomyocytes apoptosis. Matricellular proteins and HF; 'From bench to bedside'. Increasingly more genetic mutations and polyporphisms related with several important phenotype-genotype-associations are being discovered to play a possible role in the pathogenesis of cardiomyopathy. Our group discovered 1 - yet unpublished - mutation in the TSP2-gene of a patient with DCM. This variant predicted to alter the properties of the heparin-binding site in TSP2. In addition, we have found 6 new TSP2-gene polymorphisms next to the published ones, altering gene-transcription and mRNA splicing. This suggests that TSP2 could possibly also serva as an important diagnostic tool in some cases of otherwise idiopathic DCM in humans. Major aims: Do TSP2 and SPARC protect against aging of the heart and prevent pump dysfunction during myocarditis, MI and hypertension?
Date:1 Oct 2008 →  30 Sep 2009
Keywords:Heart failure, Matricellular proteins, Cardiomyopathy, Genetics, Woundhealing
Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences, Other biological sciences, Cardiac and vascular medicine