NCAM(CD56) and RUNX1(AML1) Are Up-Regulated in Human Ischemic Cardiomyopathy and a Rat Model of Chronic Cardiac Ischemia

• Published in: The American journal of pathology Vol. 163; no. 3; pp. 1081 - 1090
• Main Authors: Gattenlöhner, Stefan, Waller, Christiane, Ertl, Georg, Bültmann, Burkhard-Dieter, Müller-Hermelink, Hans-Konrad, Marx, Alexander
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.09.2003; ASIP; American Society for Investigative Pathology
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Cardiology. Vascular system; CD56 Antigen - genetics; CD56 Antigen - metabolism; Cell Adhesion Molecules - metabolism; Child; Chronic Disease; Core Binding Factor Alpha 2 Subunit; Coronary heart disease; Disease Models, Animal; DNA-Binding Proteins - metabolism; Female; Heart; Humans; Male; Medical sciences; Middle Aged; Myocardial Ischemia - genetics; Myocardial Ischemia - metabolism; Myocardial Ischemia - pathology; Promoter Regions, Genetic; Proto-Oncogene Proteins; Rats; Regular; Transcription Factors - metabolism; Up-Regulation; Human; Immunohistochemistry; Animal model; Neural cell adhesion molecule; Rat; Cardiomyopathy; Pathogenesis; Rodentia; Cell adhesion molecule; Cardiovascular disease; Coronary heart disease; Myocardial disease; Vascular disease; Anatomic pathology; Vertebrata; Mammalia; Ischemia; Animal; DNA; Library; Molecular biology; Transcription factor
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)63467-0

Chronic myocardial ischemia is the leading cause of impaired myocardial contractility and heart failure. To identify differentially expressed genes in human ischemic cardiomyopathy (ICM), we constructed a subtracted cDNA library using specimens of ICM compared to normal human heart. Among 100 randomly sequenced clones, seven sequences represented recently identified candidate genes for differential expression in cardiac hypertrophy. A further clone without a known hypertrophy-association coded for the adhesion molecule NCAM(CD56). RNase protection assay, immunohistochemistry, and Western blotting revealed strong overexpression of NCAM(CD56) in all hearts with ICM ( n = 14) compared to normal hearts ( n = 8), whereas in congestive cardiomyopathy (CCM) ( n = 8), hypertrophic obstructive cardiomyopathy ( n = 2), myocarditis ( n = 4), and sarcoidosis ( n = 2), at most slight overexpression of NCAM(CD56) was observed. NCAM(CD56) overexpression abnormally involved the whole cell membrane and the cytoplasma of cardiomyocytes only inside and adjacent to ischemia-induced cardiac scars. Normal or hypertrophic fibers at a distance from ischemic scars were devoid of NCAM overexpression. Identical alterations were observed in an experimental rat ICM model, but not in normal nor in spontaneously hypertensive rat hearts. In search of NCAM(CD56)-related transcription factors we found RUNX1(AML1) up-regulation in ICM and detected RUNX1(AML1) binding within the NCAM(CD56) promoter by electromobility shift assay. We concluded that strong overexpression of NCAM(CD56) and RUNX1(AML1) is a constant and characteristic feature of cardiomyocytes within or adjacent to scars in ICM.