Waspe L E, Ordahl C P, Simpson P C
Division of Cardiology, Veterans Administration Medical Center, San Francisco, California 94121.
J Clin Invest. 1990 Apr;85(4):1206-14. doi: 10.1172/JCI114554.
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.
压力超负荷在体内所引发的心肌肥大，其特征在于胎儿/新生儿β-心肌肌球蛋白重链（MHC）同基因的选择性上调。然而，尚未确定β-MHC同基因诱导的分子信号。我们在一种心肌肥大的细胞培养模型中检测了心脏MHC同基因的表达。在由α1-肾上腺素能激动剂去甲肾上腺素（NE）刺激引起的心肌肥大过程中，对培养的心肌细胞中的α-MHC和β-MHC同工蛋白及同工mRNA水平进行了定量分析。与对照组相比，β-MHC同工蛋白含量增加了3.2倍（P<0.001），而α-MHC同工蛋白含量无显著变化（为对照组的1.4倍，P=无显著性差异）。使用单一寡核苷酸探针通过核酸酶S1分析对MHC同工mRNA水平进行定量。与对照组相比，NE使β-MHC同工mRNA含量增加了3.9倍（P<0.001），但α-MHC同工mRNA无变化（为对照组的1.1倍，P=无显著性差异）。NE刺激引起的β-MHC同工mRNA增加在时间上先于β-MHC同工蛋白积累的增加。NE诱导β-MHC的半数有效浓度（EC50）为40 nM，药理学实验表明具有α1-肾上腺素能受体特异性。在对照心肌细胞中α-MHC同基因表达占主导（68%α-同工蛋白和60%α-同工mRNA）。相反，在用NE处理后，β-MHC表达与α-MHC相等或占主导（51%β-同工蛋白和69%β-同工mRNA）。因此，在培养的新生大鼠心肌细胞肥大过程中，α1-肾上腺素能受体刺激增加了β-MHC同工mRNA和β-MHC同工蛋白的细胞含量，但未改变α-MHC同工mRNA或同工蛋白的水平。对β-MHC的影响主要在mRNA稳态水平（翻译前）介导。α1-肾上腺素能受体的激活是在心肌肥大模型中第一个被确定的β-MHC同基因表达增加的分子信号。
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