title: The 140-kD isoform of CD56 (NCAM1) directs the molecular pathogenesis of ischemic cardiomyopathy.
abstract: Despite recent advances in understanding the relevance of cell adhesion-related signaling in the pathogenesis of ischemic cardiomyopathy (ICM) in animal models, substantial questions remain unanswered in the human setting. We have previously shown that the neural cell adhesion molecule CD56 [neural cell adhesion molecule (NCAM1)] is specifically overexpressed in ICM; it was the aim of the current study to further elucidate the role of CD56 in the pathogenesis of human ICM. We used quantitative real-time PCR and IHC in human ICM and a rat model of coronary obstruction to demonstrate that CD56(140kD), the only extraneuronally expressed NCAM1 isoform with a cytoplasmic protein domain capable of inducing intracellular signaling, is the only up-regulated CD56 isoform in failing cardiomyocytes in human ICM in vivo. In subsequent analyses of the cellular effects of CD56(140kD) overexpression in the development of ICM using differential whole transcriptome expression analyses and functional in vitro cardiomyocyte cell culture assays, we further show that the up-regulation of CD56(140kD) is associated with profound gene expression changes, increased apoptosis, and reduced Ca(2+) signaling in failing human cardiomyocytes. Because apoptosis and Ca(2+)-related sarcomeric dysfunction are molecular hallmarks of ICM in humans, our results provide strong evidence that CD56(140kD) up-regulation plays a pivotal role in the pathogenesis of ICM and may be a target for future immunotherapeutic strategies in the treatment of this common and often fatal disease.
authors: Institute of Pathology, University of Giessen, D-35392 Giessen, Germany.
authors: Mehmet Kemal
authors: MK
authors: Tur
authors: Benjamin
authors: B
authors: Etschmann
authors: Alexander
authors: A
authors: Benz
authors: Ellen
authors: E
authors: Leich
authors: Christiane
authors: C
authors: Waller
authors: Kai
authors: K
authors: Schuh
authors: Andreas
authors: A
authors: Rosenwald
authors: Georg
authors: G
authors: Ertl
authors: Anne
authors: A
authors: Kienitz
authors: Andre T
authors: AT
authors: Haaf
authors: Andreas
authors: A
authors: Bräuninger
authors: Stefan
authors: S
authors: Gattenlöhner
mesh_terms: D000818:Animals; D017209:Apoptosis; D019002:CD56 Antigen / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D009202:Cardiomyopathies / Q000150:complications / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D008970:Molecular Weight; D050505:Mutant Proteins / Q000378:metabolism; D017202:Myocardial Ischemia / Q000150:complications / Q000235:genetics / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D019002:CD56 Antigen; D050505:Mutant Proteins; C522918:NCAM1 protein, human; D020033:Protein Isoforms; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium