AIMS Sialylation is up-regulated during the development of cardiac hypertrophy. Sialyltransferase7A (Siat7A) mRNA is consistently over-expressed in the hypertrophic left ventricle of hypertensive rats independently of genetic background. The aims of this study were: (i) to detect the Siat7A protein levels and its roles in the pathological cardiomyocyte hypertrophy; (ii) to elucidate the effect of sialylation mediated by Siat7A on the transforming-growth-factor-β-activated kinase (TAK1) expression and activity in cardiomyocyte hypertrophy; and (iii) to clarify hypoxia-inducible factor 1 (HIF-1) expression was regulated by Siat7A and transactivated TAK1 expression in cardiomyocyte hypertrophy. METHODS AND RESULTS Siat7A protein level was increased in hypertrophic cardiomyocytes of human and rats subjected to chronic infusion of angiotensin II (ANG II). Delivery of adeno-associated viral (AAV9) bearing shRNA against rat Siat7A into the left ventricular wall inhibited ventricular hypertrophy. Cardiac-specific Siat7A overexpression via intravenous injection of an AAV9 vector encoding Siat7A under the cardiac troponin T (cTNT) promoter aggravated cardiac hypertrophy in ANG II-treated rats. In vitro, Siat7A knockdown inhibited the induction of Sialyl-Tn (sTn) antigen and cardiomyocyte hypertrophy stimulated by ANG II. Mechanistically, ANG II induced the activation of TAK1-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling in parallel to up-regulation of Siat7A in hypertrophic cardiomyocytes. Siat7A knockdown inhibited activation of TAK1-NF-κB pathway. Interestingly, HIF-1α expression was increased in cardiomyocytes stimulated by ANG II but decreased after Siat7A knockdown. HIF-1α knockdown efficiently decreased TAK1 expression. ChIP and luciferase assays showed that HIF-1α transactivated the TAK1 promoter region (nt -1285 to -1274 bp) in the cardiomyocytes following ANG II stimulus. CONCLUSION Siat7A was up-regulated in hypertrophic myocardium and promoted cardiomyocyte hypertrophy via activation of the HIF-1α-TAK1-NF-κB pathway.

中文翻译：

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唾液酸转移酶7A通过HIF-1α-TAK1信号通路促进血管紧张素II诱导的心肌肥大。

在心脏肥大的发展过程中，AIMS唾液酸化水平上调。唾液酸转移酶7A（Siat7A）mRNA始终在高血压大鼠肥厚性左心室中过表达，而与遗传背景无关。这项研究的目的是：（i）检测Siat7A蛋白水平及其在病理性心肌细胞肥大中的作用；（ii）阐明Siat7A介导的唾液酸化对心肌细胞肥大中转化生长因子β活化激酶（TAK1）表达和活性的影响；（iii）阐明缺氧诱导因子1（HIF-1）的表达受Siat7A调节并在心肌肥大中被反式激活了TAK1的表达。方法和结果长期输注血管紧张素II（ANG II）的人和大鼠的肥厚型心肌细胞中，Siat7A蛋白水平升高。将针对大鼠Siat7A的带有shRNA的腺相关病毒（AAV9）传递到左心室壁可抑制心室肥大。通过在心脏肌钙蛋白T（cTNT）启动子下静脉内注射编码Siat7A的AAV9载体，心脏特异性Siat7A过表达会加剧ANG II治疗的大鼠的心肌肥大。在体外，Siat7A敲低抑制了ANG II刺激的Sialyl-Tn（sTn）抗原的诱导和心肌肥大。从机制上讲，ANG II诱导了肥大型心肌细胞中Siat7A上调的同时，还激活了活化B细胞（NF-κB）信号传导的TAK1核因子κ-轻链增强子的激活。Siat7A组合式抑制TAK1-NF-κB途径的激活。有趣的是，HIF-1α表达在ANG II刺激的心肌细胞中增加，但在Siat7A敲低后降低。HIF-1α敲低有效地降低了TAK1的表达。ChIP和荧光素酶分析表明，HANG-1α在ANG II刺激后使心肌细胞中的TAK1启动子区域（nt -1285至-1274 bp）反式激活。结论Siat7A在肥厚性心肌中上调，并通过激活HIF-1α-TAK1-NF-κB途径促进心肌肥大。ChIP和荧光素酶分析表明，HANG-1α在ANG II刺激后使心肌细胞中的TAK1启动子区域（nt -1285至-1274 bp）反式激活。结论Siat7A在肥厚性心肌中上调，并通过激活HIF-1α-TAK1-NF-κB途径促进心肌肥大。ChIP和荧光素酶分析表明，HANG-1α在ANG II刺激后使心肌细胞中的TAK1启动子区域（nt -1285至-1274 bp）反式激活。结论Siat7A在肥厚性心肌中上调，并通过激活HIF-1α-TAK1-NF-κB途径促进心肌肥大。