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 β-cardiac myosin heavy chain (MHC) isogene. However, a molecular signal for β-MHC isogene induction has not been identified. We examined cardiac MHC isogene expression in a cell culture model for hypertrophy. α-MHC and β-MHC isoprotein and iso-mRNA levels in cultured cardiac myocytes were quantified during hypertrophy stimulated by the α1-adrenergic agonist, norepinephrine (NE). β-MHC iso-protein content was increased 3.2-fold vs. control (P < 0.001), whereas α-MHC isoprotein content was not changed significantly (1.4-fold vs. control, P = NS). MHC iso-mRNA levels were quantified by nucleate S1 analysis, using a single oligonucleotide probe. NE increased β-MHC iso-mRNA content by 3.9-fold vs. control (P < 0.001), but there was no change in α-MHC iso-mRNA (1.1-fold vs. control, P = NS). The NE-stimulated increase in β-MHC iso-mRNA preceded in time the increase in β-MHC isoprotein accumulation. The EC50 for NE induction of β-MHC was 40 nM, and pharmacologic experiments indicated α1-adrenergic receptor specificity. α-MHC isogene expression was predominant in control myocytes (68% α-isoprotein and 60% α-iso-mRNA). In contrast, β-MHC expression was equal to α-MHC or predominant after treatment with NE (51% β-isoprotein and 69% β-iso-mRNA). Thus, α1-adrenergic receptor stimulation increases the cellular contents of β-MHC iso-mRNA and β-MHC isoprotein during hypertrophy of cultured neonatal rat cardiac myocytes, but does not change the levels of α-MHC iso-mRNA or isoprotein. The effect on β-MHC is mediated primarily at the level of mRNA steady-state level (pretranslational). Activation of the α1-adrenergic receptor is the first identified molecular signal for increased β-MHC isogene expression in a model of cardiac hypertrophy.