Cardiac hypertrophy is widely diagnosed in clinical cardiac disorders. The pathophysiology of hypertrophy is complex and multifactorial, a series of molecular and cellular changes are participated, such as activation of different signaling pathways, a switch of fetal gene program in the myocardium, and apoptosis. Some biomarkers have been applied to assess cardiac hypertrophy including atrial natriuretic peptides (ANP), brain/B-type natriuretic peptides (BNP), and α- or β- Myosin Heavy Chain (MHC) in addition to others. Recently, ubiquitin-protein ligase E3A (UBE3A) has been observed to increase in cardiac hypertrophy. Therefore, UBE3A as a new biomarker seems valuable in the clinic. The cardiac hypertrophy is induced in rat-derived heart cell line H9c2 cells by potassium bromate (KBrO3), high glucose (HG), or isoproterenol (Iso), respectively. As an oxidizing agent, KBrO3 increased cell size at concentrations less than 250 μM. Similarly, HG and Iso also induced cardiac hypertrophy in H9c2 cells. Interestingly, each kind of the cell models promoted the gene expression of the well-known biomarkers of cardiac hypertrophy including atrial natriuretic peptides (ANP) and brain/B-type natriuretic peptides (BNP). Additionally, UBE3A is also raised with the signals involved in cardiac hypertrophy such as calcineurin and nuclear factor of activated T-cells (NFAT) determined using Western blots. KBrO3 increased the protein levels of these signals and the specific inhibitor, such as cyclosporine A and tacrolimus, attenuated the signaling in H9c2 cells at concentrations sufficient to inhibit calcineurin in addition to the reduction of mRNA levels of UBE3A, similar to ANP or BNP. Moreover, HG or Iso also significantly increased protein levels of UBE3A in H9c2 cells. Taken together, we provided a new view that UBE3A is markedly raised in cardiac hypertrophy using various cell models, mainly through the activation of the calcineurin/NFAT signaling pathway in H9c2 cells. Therefore, UBE3A could be developed as a new biomarker in the diagnosis of cardiac hypertrophy.

中文翻译：

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泛素蛋白连接酶 E3a (UBE3A) 作为细胞模型中心脏肥大的新生物标志物

心脏肥大在临床心脏疾病中被广泛诊断。肥大的病理生理是复杂的、多因素的，参与了一系列分子和细胞的变化，如不同信号通路的激活、心肌中胎儿基因程序的转换、细胞凋亡等。一些生物标志物已被用于评估心脏肥大，包括心房利钠肽 (ANP)、脑/B 型利钠肽 (BNP) 和 α- 或 β- 肌球蛋白重链 (MHC) 等。最近，观察到泛素蛋白连接酶 E3A (UBE3A) 会增加心脏肥大。因此，UBE3A作为一种新的生物标志物在临床上似乎很有价值。分别由溴酸钾 (KBrO3)、高葡萄糖 (HG) 或异丙肾上腺素 (Iso) 在大鼠衍生的心脏细胞系 H9c2 细胞中诱导心脏肥大。作为氧化剂，KBrO3 在浓度低于 250 μM 时会增加细胞大小。同样，HG 和 Iso 也诱导 H9c2 细胞的心脏肥大。有趣的是，每种细胞模型都促进了众所周知的心脏肥大生物标志物的基因表达，包括心房利钠肽（ANP）和脑/B型利钠肽（BNP）。此外，UBE3A 也随着与心肌肥大有关的信号而升高，例如使用蛋白质印迹测定的钙调神经磷酸酶和活化 T 细胞的核因子 (NFAT)。KBrO3 增加了这些信号的蛋白质水平，并且特异性抑制剂（如环孢素 A 和他克莫司）在 H9c2 细胞中减弱了信号，其浓度足以抑制钙调神经磷酸酶，此外还降低了 UBE3A 的 mRNA 水平，类似于 ANP 或 BNP。而且，HG 或 Iso 也显着增加了 H9c2 细胞中 UBE3A 的蛋白质水平。总之，我们提供了一个新的观点，即使用各种细胞模型，UBE3A 在心脏肥大中显着升高，主要是通过激活 H9c2 细胞中的钙调神经磷酸酶/NFAT 信号通路。因此，UBE3A 可作为诊断心脏肥大的新生物标志物。