Transcription of early developmental isogenes in cardiac myocyte hypertrophy

• Published in: Journal of molecular and cellular cardiology Vol. 21; pp. 79 - 89
• Main Authors: Simpson, Paul C., Long, Carlin S., Waspe, Lawrence E., Henrich, Curtis J., Ordahl, Charles P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.1989
• Subjects: Actin; Animals; Cardiac myocyte; Cardiomegaly - etiology; Cardiomegaly - genetics; Cardiomegaly - physiopathology; Cell culture; Cells, Cultured; Gene expression; Hypertrophy; Models, Genetic; Muscle Proteins - biosynthesis; Muscle Proteins - genetics; Myosin; Protein kinase C; Protein Kinase C - physiology; Rats; Receptors, Adrenergic, alpha - physiology; Transcription; Transcription, Genetic; Up-Regulation; α1-adrenergic receptor; Cell culture; Protein kinase C; Transcription; Actin; α 1-adrenergic receptor; Myosin; Cardiac myocyte; Gene expression; Hypertrophy
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/0022-2828(89)90774-8

We have developed a cell culture system to study molecular mechanisms important in myocardial hypertrophy. α 1-Adrenergic receptor stimulation produces hypertrophy of neonatal rat cardiac myocytes. Myocyte hyperplasia is not induced by α 1 stimulation, although α 1-adrenergic receptor-mediated DNA synthesis and cell division have been observed in other types of cells. The myocyte hypertrophic response does not require contractile activity. Activation of the α 1 receptor also produces highly specific alterations in gene expression, as measured at the mRNA and protein levels. In particular, there is selective up-regulation of two contractile protein isogenes that are expressed in vivo during early development and in pressure-load hypertrophy, skeletal α-actin and β-myosin heavy chain. Studies with an in vitro transcription assay indicate that stimulation of the α 1-adrenergic receptor leads to a distinctive temporal sequence of transcriptional activation. Transcription of the skeletal α-actin isogene is induced preferentially to that of cardiac α-actin. Thus, early developmental isogene induction in α 1-stimulated hypertrophy reflects a fundamental change in the transcriptional program of the cardiac myocyte nucleus. The goal now is to define an intracellular pathway connecting the α 1-adrenergic receptor in the plasma membrane to activation of RNA polymerase II on the skeletal α-actin gene in the cardiac myocyte nucleus. There is evidence that protein kinase C may be one component of this pathway. A model for α 1-mediated transcription is presented.