Center for Molecular Development and Disease, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030, USA.
Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1340-7. doi: 10.1152/ajpheart.00592.2009. Epub 2010 Feb 19.
Activation of NFAT (nuclear factor of activated T cells)-mediated hypertrophic signaling is a major regulatory response to hypertrophic stimuli. A recent study unveiled potential regulatory roles for microRNA-133a (miR-133a) in cardiac hypertrophy. To date, however, no connection has been made between miR-133a and NFAT signaling. In this study, we determined that NFATc4, a hypertrophy-associated mediator, is negatively regulated by miR-133a. Two conserved base-pairing sites between the NFATc4 3'-untranslated region (UTR) and miR-133a were verified. Mutation of these sites in the NFATc4 3'-UTR completely blocked the negative effect of miR-133a on NFATc4, suggesting that NFATc4 is a direct target for miR-133a regulation. Using a gain-of-function approach, we demonstrate that miR-133 significantly reduces the endogenous level of, as well as the hypertrophic stimulus-mediated increase in, NFATc4 gene expression. This latter effect of miR-133a on NFATc4 gene expression was coincided with an attenuated cardiomyocyte hypertrophy induced by an alpha-adrenergic receptor agonist. Conversely, cells treated with miR-133a inhibitor resulted in an increase in NFATc4 expression level. Application of miR-133a had no apparent effect on NFATc4 nuclear localization. We conclude that the negative regulation of NFATc4 expression contributes to miR-133a-mediated hypertrophic repression.
NFAT（活化 T 细胞的核因子）介导的肥大信号的激活是对肥大刺激的主要调节反应。最近的一项研究揭示了 microRNA-133a（miR-133a）在心肌肥大中的潜在调节作用。然而，迄今为止，miR-133a 与 NFAT 信号之间尚未建立联系。在这项研究中，我们确定 NFATc4，一种与肥大相关的介质，受 miR-133a 的负调控。NFATc4 3'-非翻译区（UTR）和 miR-133a 之间的两个保守碱基配对位点得到了验证。这些 NFATc4 3'-UTR 中的位点的突变完全阻断了 miR-133a 对 NFATc4 的负效应，表明 NFATc4 是 miR-133a 调节的直接靶标。使用功能获得方法，我们证明 miR-133a 显著降低了 NFATc4 基因表达的内源性水平以及肥大刺激介导的增加。miR-133a 对 NFATc4 基因表达的后一种作用与α-肾上腺素能受体激动剂诱导的心肌细胞肥大减弱相吻合。相反，用 miR-133a 抑制剂处理的细胞导致 NFATc4 表达水平增加。miR-133a 的应用对 NFATc4 的核定位没有明显影响。我们得出结论，NFATc4 表达的负调控有助于 miR-133a 介导的肥大抑制。
