Sympathetic activity: modulator of myocardial hypertrophy.
The mechanisms regulating myocardial hypertrophy are largely unknown. Furthermore, the hypertrophic phenotype can be associated with either normal or abnormal function. To study the molecular mechanisms involved in myocardial hypertrophy, we have established a cell culture system in which stimulation of the alpha 1-adrenergic receptor leads to the development of myocardial cell hypertrophy. In addition to producing a generalized twofold increase in both cell size, total protein, and total RNA, activation of the alpha 1-receptor produces specific alterations in gene expression that are reflected by changes at both the mRNA and protein levels. In particular, alpha 1 stimulation leads to an increase in the expression of the c-myc oncogene as well as a selective increase in skeletal alpha-actin and beta-myosin heavy-chain isogene expression, isoforms normally found only in fetal/neonatal hearts. Similar changes in gene expression are seen in pressure-load hypertrophy in vivo. Skeletal alpha-actin gene expression is induced preferentially to that of the cardiac actin isogene resulting from a specific preferential increase in gene transcription. Work with subtype-specific inhibitors indicates that it is a particular alpha 1-receptor subtype that is responsible for the development of hypertrophy in culture. The finding that alpha 1 stimulation leads to an increase in protein kinase C activity is suggestive of a potential second messenger involving the phosphorylation of a transcriptional factor or factors.
Long
C S
CS
Cardiology Section, Veterans Administration Medical Center, San Francisco, CA 94121.
Kariya
K
K
Karns
L
L
Simpson
P C
PC
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D002395:Catecholamines / Q000494:pharmacology* / Q000502:physiology; D002478:Cells, Cultured; D008955:Models, Cardiovascular; D010641:Phenotype; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D015398:Signal Transduction
D002395:Catecholamines; D011942:Receptors, Adrenergic, alpha