The cardiac beta-myosin heavy chain isogene is induced selectively in alpha 1-adrenergic receptor-stimulated hypertrophy of cultured rat heart myocytes.
Cardiac hypertrophy produced in vivo by pressure overload is characterized by selective up-regulation of the fetal/neonatal beta-cardiac myosin heavy chain (MHC) isogene. However, a molecular signal for beta-MHC isogene induction has not been identified. We examined cardiac MHC isogene expression in a cell culture model for hypertrophy. alpha-MHC and beta-MHC iso-protein and iso-mRNA levels in cultured cardiac myocytes were quantified during hypertrophy stimulated by the alpha 1-adrenergic agonist, norepinephrine (NE). beta-MHC iso-protein content was increased 3.2-fold vs. control (P less than 0.001), whereas alpha-MHC isoprotein content was not changed significantly (1.4-fold vs. control, P = NS). MHC iso-mRNA levels were quantified by nuclease S1 analysis, using a single oligonucleotide probe. NE increased beta-MHC iso-mRNA content by 3.9-fold vs. control (P less than 0.001), but there was no change in alpha-MHC iso-mRNA (1.1-fold vs. control, P = NS). The NE-stimulated increase in beta-MHC iso-mRNA preceded in time the increase in beta-MHC isoprotein accumulation. The EC50 for NE induction of beta-MHC was 40 nM, and pharmacologic experiments indicated alpha 1-adrenergic receptor specificity. alpha-MHC isogene expression was predominant in control myocytes (68% alpha-isoprotein and 60% alpha-iso-mRNA). In contrast, beta-MHC expression was equal to alpha-MHC or predominant after treatment with NE (51% beta-isoprotein and 69% beta-iso-mRNA). Thus, alpha 1-adrenergic receptor stimulation increases the cellular contents of beta-MHC iso-mRNA and beta-MHC isoprotein during hypertrophy of cultured neonatal rat cardiac myocytes, but does not change the levels of alpha-MHC iso-mRNA or isoprotein. The effect on beta-MHC is mediated primarily at the level of mRNA steady-state level (pretranslational). Activation of the alpha 1-adrenergic receptor is the first identified molecular signal for increased beta-MHC isogene expression in a model of cardiac hypertrophy.
Waspe
L E
LE
Division of Cardiology, Veterans Administration Medical Center, San Francisco, California 94121.
Ordahl
C P
CP
Simpson
P C
PC
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005318:Fetal Heart / Q000378:metabolism; D015870:Gene Expression; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000032:analysis / Q000235:genetics*; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D011942:Receptors, Adrenergic, alpha; D009218:Myosins; D009638:Norepinephrine