Abstract 10847: Neural Cell Adhesion Molecule is a Cardioprotective Factor Up-regulated In Rodent and Human Failing Heart
Purpose: Failing heart is characterized by alteration in energy metabolism, including mitochondrial dysfunction. While, membrane proteins have been a considerable interest because these proteins have potential for new biomarkers and therapeutic targets. Thus, we set up a screening method to identify a cell-surface protein whose expression was enhanced under treatment with oligomycin, a mitochondrial respiratory chain inhibitor.
Methods and results: We performed a signal sequence trap in combination with a functional cloning method and identified neural cell adhesion molecule (NCAM, CD56) as a candidate. We examined the NCAM expression in Dahl salt-sensitive rats at left ventricular hypertrophy (LVH) and chronic heart failure (CHF) periods. NCAM expression was enhanced in LVH stage by 3.0 fold (P<0.01) and further increased by 24.1 fold (P<0.001) in CHF stage. Immunohistochemical analysis revealed that strong NCAM staining was observed in subendomyocardium surrounding fibrotic area. To investigate the role of NCAM in cardiac myocytes, we introduced siRNA against NCAM by lentivirus. Survival rate of cardiac myocytes treated with oligomycin was significantly reduced when NCAM was knocked down (86% to 54.6%, P<0.05). On the other hand, stimulation of NCAM with synthetic peptide increased the survival rates of cardiac myocytes via AKT-mediated pathway, suggesting the protective role of endogenous NCAM. We also analyzed NCAM expression in 80 human samples obtained from LV endomyocardial biopsies. Patients were divided into 2 groups based on the histological result (NCAM-high n=40; NCAM-low n=40). Similarly with animal models, weak staining of NCAM was restricted in the intercalated disks in normal-appearing myocardium while, in areas of increased cardiac fibrosis, strong staining of NCAM was observed in the remaining cardiac myocytes within or adjacent to fibrotic area. The extent of histologically determined fibrosis (%area) and end-diastolic LV volume index were significantly larger in NCAM-high group than in NCAM-low group (15.5±2.5% vs. 30.1±4.0%, P<0.005, 99.2 ± 4.5ml/m2 vs. 120.8±9.0 ml/m2, P<0.05, respectively).
Conclusion: NCAM, which has a cardioprotective role, is expressed extensively in the stressed myocardium.
- © 2012 by American Heart Association, Inc.