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首页> 外文期刊>American Journal of Physiology >A beta1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction.
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A beta1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction.

机译：β1肾上腺素能受体CaM激酶II依赖性途径介导心肌细胞胎儿基因的诱导。

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摘要

Beta-adrenergic signaling plays an important role in the natural history of dilated cardiomyopathies. Chronic activation of beta-adrenergic receptors (beta1-AR and beta2-AR) during periods of cardiac stress ultimately harms the failing heart by mechanisms that include alterations in gene expression. Here, we show that stimulation of beta-ARs with isoproterenol in neonate rat ventricular myocytes causes a "fetal" response in the relative activities of the human cardiac fetal and/or adult gene promoters that includes repression of the human and rat alpha-myosin heavy chain (alpha-MyHC) promoters with simultaneous activation of the human atrial natriuretic peptide (ANP) and rat beta-MyHC promoters. We also show that the promoter changes correlate with changes in endogenous gene expression as measured by mRNA expression. Furthermore, we show that these changes are specifically mediated by the beta1-AR, but not the beta2-AR, and are independent of alpha1-AR stimulation. We also demonstrate that the fetal gene response is independent of cAMP and protein kinase A, whereas inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK) pathway blocks isoproterenol-mediated fetal gene program induction. Finally, we show that induction of the fetal program is dependent on activation of the L-type Ca2+ channel. We conclude that in neonatal rat cardiac myocytes, agonist-occupied beta1-AR mobilizes Ca2+ stores to activate fetal gene induction through cAMP independent pathways that involve CaMK.
机译：β-肾上腺素能信号传导在扩张型心肌病的自然病史中起着重要作用。在心脏压力期间，β-肾上腺素能受体（β1-AR和β2-AR）的慢性活化最终会通过包括基因表达改变在内的机制损害心脏衰竭。在这里，我们显示在新生大鼠心室肌细胞中用异丙肾上腺素刺激β-ARs会在人心脏胎儿和/或成年基因启动子的相对活动中引起“胎儿”反应，包括抑制人和大鼠α-肌球蛋白重链（α-MyHC）启动子，同时激活人心钠素和大鼠β-MyHC启动子。我们还显示，启动子的变化与内源基因表达的变化相关，如通过mRNA表达所测。此外，我们显示这些更改是由beta1-AR而不是beta2-AR专门介导的，并且独立于alpha1-AR刺激。我们还证明了胎儿基因应答独立于cAMP和蛋白激酶A，而对Ca2 + /钙调蛋白依赖性蛋白激酶（CaMK）通路的抑制则阻断了异丙肾上腺素介导的胎儿基因程序的诱导。最后，我们证明了胎儿程序的诱导取决于L型Ca2 +通道的激活。我们得出的结论是，在新生大鼠心肌细胞中，激动剂占据的β1-AR能够动员Ca2 +存储，从而通过涉及CaMK的cAMP独立途径激活胎儿基因诱导。

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