唾液酸转移酶 7A 通过 HIF-1α-TAK1 信号通路促进血管紧张素 II 诱导的心肌细胞肥大。
Sialyltransferase7A promotes angiotensin II-induced cardiomyocyte hypertrophy via HIF-1α-TAK1 signalling pathway.
机构信息
Department of Physiology, Dalian Medical University, Lvshun South Road No.9, Dalian, Liaoning, People's Republic of China.
Functional Laboratory, Dalian Medical University, Dalian, People's Republic of China.
出版信息
Cardiovasc Res. 2020 Jan 1;116(1):114-126. doi: 10.1093/cvr/cvz064.
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.
目的
唾液酸化在心脏肥大的发展过程中上调。唾液酸转移酶 7A（Siat7A）mRNA 在高血压大鼠的肥厚左心室中始终过度表达，与遗传背景无关。本研究的目的是：（i）检测 Siat7A 蛋白水平及其在病理性心肌肥厚中的作用；（ii）阐明 Siat7A 介导的唾液酸化对心肌肥厚中转化生长因子-β激活激酶（TAK1）表达和活性的影响；（iii）阐明缺氧诱导因子 1（HIF-1）表达受 Siat7A 调节并在心肌肥厚中转导 TAK1 表达。
方法和结果
在人类和接受慢性血管紧张素 II（ANG II）输注的大鼠的肥厚心肌细胞中，Siat7A 蛋白水平增加。将携带针对大鼠 Siat7A 的短发夹 RNA 的腺相关病毒（AAV9）递送至左心室壁，可抑制心室肥厚。通过静脉注射携带心脏肌钙蛋白 T（cTNT）启动子的 AAV9 载体表达 Siat7A，可加重 ANG II 处理大鼠的心脏肥厚。在体外，Siat7A 敲低抑制了 ANG II 诱导的 Sialyl-Tn（sTn）抗原和心肌细胞肥大的诱导。在机制上，ANG II 在肥厚心肌细胞中诱导 TAK1-核因子 κB（NF-κB）信号通路的激活与 Siat7A 的上调平行。Siat7A 敲低抑制了 TAK1-NF-κB 通路的激活。有趣的是，在 ANG II 刺激的心肌细胞中 HIF-1α 的表达增加，但在 Siat7A 敲低后减少。HIF-1α 敲低可有效降低 TAK1 的表达。ChIP 和荧光素酶测定表明，HIF-1α 在 ANG II 刺激后可转激活心肌细胞中 TAK1 启动子区域（nt-1285 至-1274bp）。
结论
Siat7A 在肥厚心肌中上调，并通过激活 HIF-1α-TAK1-NF-κB 通路促进心肌细胞肥大。
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