Since the beginning of his career, Stephane Heymans has been fascinated by the mechanisms underlying heart failure. During his training as a cardiologist and scientist, he met several young patients that had severe unexplained heart dilated cardiomyopathy, or died suddenly due to viral myocarditis. This triggered his interest to unravel the poorly understood mechanisms for heart failure in general and the susceptibility to viral myocarditis and dilated cardiomyopathy in particular.
His group put forwards the matri-cellular proteins and microRNAs as novel therapeutic targets to tackle inflammation and adverse remodelling in the heart. Accordingly, the primary aim of his program is to delineate the role of these matricellular proteins and microRNAs, and find new molecular mechanisms and diagnostic markers for inflammation due to hypertensive and ischemic HF, as well as for primary inflammation due to viral myocarditis.
In 2006, he started a trans-disciplinary clinical program on viral and inflammatory cardiomyopathies, which brings together immunologists, microbiologists, pathologists and molecular cardiologists to study the role of inflammation, matrix remodelling and cardiomyocyte biology in viral myocarditis. As such, knowledge obtained in basic research is continuously translated to human pathology and vice versa, in order to relate pre-clinical findings to molecular, functional and structural data in human hearts.
Matricellular proteins and heart failure (Senior Postdoc Dr. Anna Papageourgiou)
Two important systems in the matrix are the structural proteins like collagens, and the non structural proteins, the matricellular proteins. Increased expression of matrixmetalloproteinases (MMPs) during HF causes degradation of collagen fibers, myocyte slippage and increased inflammation, whereas enhanced expression of matricellular proteins are protective, by promoting myocyte survival, decreasing inflammation, and stimulating the production of a qualitative matrix. These matricellular proteins are a group of non-structural glycoproteins present in the interstitial matrix, including thrombospondins, mimecan, stabilin-1 and SPARC (osteonectin), among others. They do not play a direct structural role in the heart, but regulate interactions between the matrix and cardiomyocytes, fibroblasts and inflammatory cells. Their expression is low in the normal heart, but reappears at high levels during cardiac injury or stress, such as hypertension and ischemia. The researchprogram obtained strong evidence that matricellular proteins protect against the adverse inflammatory response during hypertensive and ischemic heart disease. This is substantiated by the more pronounced inflammatory, hypertrophic and fibrotic response in the hearts of micelacking the matrix proteins thrombospondin-2, mimecan, stabilin-1 or osteonectin (SPARC). These findings indicate that inflammatory cells interact with cardiomyocytes and fibroblasts, and that matrix proteins produced by these inflammatory cells regulate the crosstalk towards hypertrophic and pro-fibrotic signaling pathways. Therefore, the primary aims of this program are to unravel the implication of the matricellular proteins at the level of each individual cardiac cell: inflammatory cells, fibroblasts, cardiomyocytes and endothelial cells. The molecular mechanisms by which these matricellular proteins altercardiomyocyte survival/hypertrophy, promote matrix maturation, and prevent adverse inflammation will be addressed. We aim to find out which molecular partners on cell membrane are regulating their protective effect on cardiomyocyte survival, the downstream signaling cascade and the resulting changes in hypertrophy, inflammatory andfibrotic targets.
The Netherlands Heart Foundation (3 ongoing research grants), the Flemish Research Foundation (FWO, 1 ongoing research grant), the Netherlands Research Foundation (NWO, very prestigious personal Vidi grant to Prof. S. Heymans in 2008), and the European Community (MEDIA, coordinated program, 2010) granted this work.
Inflammation-mediated microRNA’s and cardiac disease (Senior Investigator B. Schroen)
Last 3 years, because of his inner interest on cardiac inflammation and HF, Dr. Blanche Schroen, with the help of Frank Stassen, opened a completely new area of research, investigating the yet unknown role for inflammation-related microRNA’s in heart failure in general, and viral myocarditis in particular (at this time 0 hits in www.pubmed.com). A major microarray analysis of microRNA’s at different time points of viral myocarditis, pressure overload and dilated cardiomyopathy was performed both in mice and humans, unravelling major inflammation microRNA signals, and identifying novel microRNA targets implicated in cardiac inflammation and HF.
The overall objective of this research line is to unravel the precise biological role of specific inflammation-mediated microRNA’s (microRNA’s) and their regulation in cardiac injury and dysfunction following viral infection, and in hypertrophy and fibrosis during hypertensive heart disease. Whereas recent studies mainly focused on the role of cardiomyocyteand fibroblast-derived microRNA’s in hypertrophy, fibrosis and arrhythmias, this program will unravel the biological role of the inflammation-derived microRNA’s in cardiac disease. By combining microRNA knockout animal experiments, the use of antagomirs, and in vitro studies, this program is currently addressing the role of particular inflammation derived microRNA’s in both hypertensive heart disease and viral myocarditis. It is expected that inflammation-mediated microRNA’s play a crucial role in the susceptibility to cardiac injury following viral infection of the heart, and mediate hypertrophy and fibrosis during hypertension.
Preliminary data obtained were the basis to get funding of the Netherlands Heart Foundation (1 ongoing research grant), the Flemish Research Foundation (FWO, 2 ongoing research grants), the Netherlands Research Foundation (Horizon and Veni to Dr. B. Schroen, 2008 and 2009) and the European Community (MEDIA, coordinated program, 2010).
Clinical expertise: heart failure, cardiomyopathies, myocarditis. Clinical studies. Management of translational research. Basic research: heart failure, inflammation, matrix, non-coding RNA's, myocarditis, hypertension, diastolic dysfunction.