Regulation of adverse remodelling by osteopontin in a genetic heart failure model.
ABSTRACT Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice. The hallmarks of desmin-deficient (des(-/-)) mice pathology include pronounced myocardial degeneration, extended fibrosis, and osteopontin (OPN) overexpression. We sought to identify the molecular and cellular events regulating adverse cardiac remodelling in des(-/-) mice and their potential link to OPN.
In situ hybridization, histology, and immunostaining demonstrated that inflammatory cells and not cardiomyocytes were the source of OPN. RNA profile comparison revealed that activation of inflammatory pathways, sustained by innate immunity mechanisms, predominated among all changes occurring in degenerating des(-/-) myocardium. The expression of the most highly up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160× and metalloprotease-12: 98×) was associated with heart infiltrating macrophages. To evaluate the role of OPN, we generated des(-/-)OPN(-/-) mice and compared their cardiac function and remodelling indices with those of des(-/-). Osteopontin promoted cardiac dysfunction in this model since des(-/-)OPN(-/-) mice showed 53% improvement of left ventricular function, paralleled to an up to 44% reduction in fibrosis. The diminished fibrotic response in the absence of OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 levels, associated with an impaired galectin-3 secretion by OPN-deficient infiltrating macrophages.
Cardiomyocyte death due to desmin deficiency leads to inflammation and subsequent overexpression of a series of remodelling modulators. Among them, OPN seems to be a major regulator of des(-/-) adverse myocardial remodelling and it functions at least by potentiating galectin-3 up-regulation and secretion.
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ABSTRACT: Fibroproliferative diseases of organs are poorly understood and generally lack effective anti-fibrotic treatments. Our goal was to identify the key regulatory factors in pathologic fibrosis, common between organ-based fibrotic disease. We analyzed 9 microarray datasets publicly available in the GEO datasets from lung, heart, liver and kidney fibrotic disease tissue (489 microarrays total, disease and control). We identified a set of 90 genes differentially expressed in at least five microarray datasets. We used IPA and DAVID analysis to identify gene networks and their molecular functions. A mutual information based network work activity analysis showed that a connective tissue disorders network was the most active for all types of fibrosis included in this analysis. CONCLUSION: Our analysis indicates that despite different disease manifestation, organ fibrosis share a specific set of genes suggesting the potential for a common origin.AMIA Summits on Translational Science proceedings AMIA Summit on Translational Science. 01/2012; 2012:106-15.