Transcription of early developmental isogenes in cardiac myocyte hypertrophy.
We have developed a cell culture system to study molecular mechanisms important in myocardial hypertrophy. alpha 1-Adrenergic receptor stimulation produces hypertrophy of neonatal rat cardiac myocytes. Myocyte hyperplasia is not induced by alpha 1 stimulation, although alpha 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 alpha 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 alpha-actin and beta-myosin heavy chain. Studies with an in vitro transcription assay indicate that stimulation of the alpha 1-adrenergic receptor leads to a distinctive temporal sequence of transcriptional activation. Transcription of the skeletal alpha-actin isogene is induced preferentially to that of cardiac alpha-actin. Thus, early developmental isogene induction in alpha 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 alpha 1-adrenergic receptor in the plasma membrane to activation of RNA polymerase II on the skeletal alpha-actin gene in the cardiac myocyte nucleus. There is evidence that protein kinase C may be one component of this pathway. A model for alpha 1-mediated transcription is presented.
Simpson
P C
PC
Department of Medicine, University of California, San Francisco.
Long
C S
CS
Waspe
L E
LE
Henrich
C J
CJ
Ordahl
C P
CP
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D008957:Models, Genetic; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D014158:Transcription, Genetic; D015854:Up-Regulation
D009124:Muscle Proteins; D011942:Receptors, Adrenergic, alpha; D011493:Protein Kinase C