ADAPTATIONAL RESPONSE IN TRANSCRIPTION FACTORS DURING DEVELOPMENT OF MYOCARDIAL HYPERTROPHY

Cardiac hypertrophy is characterized, among others, by the molecular e vents which selectively activate the expression of genes for contracti le proteins within individual myocardial cells. As such, myosin light chain 2 (MLC-2), which is upregulated in the hypertrophic state in bot h rat and human, serves as a marker for hypertrophy. In an attempt to investigate the gene regulatory mechanisms of this phenomenon, we test ed the hypothesis that certain transcription factors are directly invo lved in the development of cardiac hypertrophy by demonstrating the pr esence of cardiac tissue-specific regulatory elements in the 5'-flanki ng region of the MLC-2 promoter and testing them in the gel mobility s hift assay for their binding activity to nuclear proteins from hypertr ophied and normal cardiac tissue. In nuclear extracts from the ventric ular tissues of the spontaneously hypertensive rat (SHR), distinctive changes in two families of activator proteins, the A/T-rich DNA-bindin g transcription factors, myocyte enhancer factor (MEF-2) and CArG-bind ing factor, manifested in a developmentally dictated manner parallelin g the evolution of cardiac hypertrophy in these animals. Extracts isol ated from brains and skeletal muscle tissues from the same animals did not exhibit the changes in binding activity. Also, the changes were n ot apparent when a distal negative regulatory element (CSS), which con fers cardiac-specific expression, was tested in gel mobility shift ass ays. The ubiquitous TATA-binding proteins remained unchanged in compar ing SHR with the control strain WKY in the same assay. These data supp ort the notion that the expression of specific transcription factors i s modulated in response to hypertrophy related signals which execute c hanges at the gene level effecting the enrichment of certain contracti le proteins in an effort discrete and estranged from the basal transcr iption machinery. (C) 1995 Academic Press Limited