CD56 (NCAM) Induces Apoptosis and Negative Inotropy in Ischemic Cardiomyopathy.
Stefan Gattenlohner, Georg Ertl, Christine Angermann, Hans-Konrad Muller-Hermelink. Institute of Pathology, Medical University of Graz, Austria; University of Würzburg, Germany; Institute of Pathology, University of Würzburg, Germany
Background: CD56 (NCAM) belongs to the family of Ca2+-independent cell adhesion molecules, CAMs, showing abundant expression mainly in fetal neural tissues. Recently, we found that CD56 is specificially overexpressed in ischemic cardiomyopathy (ICM) and regulated by the transcription factor RUNX1 (AML1). The aim of the study was to investigate the function of the CD56 expression in ICM in particular with respect to development of heart failure.
Design: animal model for acute and chronic ischemia, RT-PCR and western Blot, stable cell transfection, micro cDNA array, FACS anaylsis and intracellular Ca+ measurements.
Results: In an animal model of acute heart ischemia we could demonstrate a complete downregulation of CD56 expression in infarcted heart tissue and its upregulation in surviving surrounding cardiomyocytes, regulated by novel RUNX1 isoforms with activating and inhibiting function on the CD56 expression. Adressing the question of its functional relevance we identified the highmolecular CD56140kDa isoform as the exclusively expressed CD56 isoform in failing human hearts among the known structural and functional highly different CD56 variants. In micro array cDNA chip analysis and subsequent quantitative RT-PCR using CD56 isoform specific stable transfectants of the murine cardiomyocyte cell line HL-1, the CD56140kDa overexpressing cardiomyoctes showed an induction of apoptosis related genes as well as downregulation of pathways related to calcium channel signalling. These data were confirmed by functional tests on human living cardiomyocytes demonstrating an increased apoptosis (5-fold) in Annexin V FACS analysis and downregulation of the proliferation in MTT assay (3-fold) as well as a reduced calcium influx (8-fold) in Fluo-4AM intracellular measurement with significantg reduction of contractility.
Conclusions: We conclude that the overxpression of CD56140kD is functionally relevant for the development of ICM and blocking of CD56140kD expression respectively its dependent signalling cascades might be a therapeutical target for the treatment of loss and insufficient contractility of cardiomyocytes in ischemic heart failure.
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 34, Wednesday Afternoon