Cardiac hypertrophy is characterized, among others, by the molecular events which selectively activate the expression of genes for
contractile proteins within individual myocardial cells. As such,
myosin light chain 2 (MLC-2), which is upregulated in the hypertrophic state in both rat and human, serves as a marker for
hypertrophy. In an attempt to investigate the gene regulatory mechanisms of this phenomenon, we tested the hypothesis that certain
transcription factors are directly involved in the development of
cardiac hypertrophy by demonstrating the presence of cardiac tissue-specific regulatory elements in the 5'-flanking region of the MLC-2 promoter and testing them in the gel mobility shift assay for their binding activity to
nuclear proteins from hypertrophied and normal cardiac tissue. In nuclear extracts from the ventricular tissues of the spontaneously hypertensive rat (SHR), distinctive changes in two families of activator
proteins, the A/T-rich
DNA-binding
transcription factors, myocyte enhancer factor (MEF-2) and CArG-binding factor, manifested in a developmentally dictated manner paralleling the evolution of
cardiac hypertrophy in these animals. Extracts isolated from brains and skeletal muscle tissues from the same animals did not exhibit the changes in binding activity. Also, the changes were not apparent when a distal negative regulatory
element (CSS), which confers cardiac-specific expression, was tested in gel mobility shift assays. The ubiquitous TATA-
binding proteins remained unchanged in comparing SHR with the control strain WKY in the same assay. These data support the notion that the expression of specific
transcription factors is modulated in response to
hypertrophy related signals which execute changes at the gene level effecting the enrichment of certain
contractile proteins in an effort discrete and estranged from the basal transcription machinery.