EGCG inhibits pressure overload-induced cardiac hypertrophy via the PSMB5/Nmnat2/SIRT6-dependent signalling pathways
EGCG inhibits pressure overload-induced cardiac hypertrophy via the PSMB5/Nmnat2/SIRT6-dependent signalling pathways
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DOI：
10.1111/apha.13602
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发表时间：
2021-01-07
影响因子：
6.3
通讯作者：
Liu, Pei Qing
中科院分区：
文献类型：
--
作者：
Cai, Yi;Yu, Shan Shan;Liu, Pei Qing
目的：表没食子儿茶素没食子酸酯(EGCG)是绿茶中的主要多酚，对包括心肌肥厚在内的心血管疾病具有多种保护作用。然而，其抗肥厚作用的分子机制尚不清楚。本研究揭示EGCG可通过调节依赖于PSMB5/Nmnat2/SIRT6的信号通路，抑制压力超负荷所致的心肌肥厚。方法：采用实时定量聚合酶链式反应和Western blotting分别检测心肌组织中PSMB5/Nmnat2/SIRT6基因和蛋白的表达。用荧光试剂盒检测组蛋白脱乙酰酶SIRT6的活性。结果：EGCG能显著提高血管紧张素II(Ang II)刺激的新生大鼠心肌细胞和腹主动脉缩窄大鼠心脏组织中Nmnat2蛋白的表达和酶活性。RNA干扰下调Nmnat2基因可减弱EGCG对心肌肥厚的抑制作用。EGCG阻断Ang II诱导的NF-kappa B DNA结合活性，这依赖于Nmnat2和随后的SIRT6激活。此外，EGCG诱导的Nmnat2蛋白表达还需要PSMB5(20S蛋白酶体亚基β-5，类糜蛋白酶)的激活。此外，我们还证实了EGCG可能与PSMB5相互作用并抑制蛋白水解酶的激活。结论：首次证明EGCG的抗心肌肥厚作用可能至少部分归因于对PSMB5/Nmnat2依赖的信号通路的调节，提示EGCG在预防和治疗心肌肥厚方面具有潜在的治疗潜力。
Aim: Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, exerts multiple protective effects against cardiovascular diseases, including cardiac hypertrophy. However, the molecular mechanism underlying its anti-hypertrophic effect has not been clarified. This study revealed that EGCG could inhibit pressure overload-induced cardiac hypertrophy by regulating the PSMB5/Nmnat2/SIRT6-dependent signalling pathway.Methods: Quantitative real-time polymerase chain reaction and western blotting were used to determine the expression of mRNA and protein respectively. A fluorometric assay kit was used to determine the activity of SIRT6, a histone deacetylase. Luciferase reporter gene assay and electrophoretic mobility shift assay were employed to measure transcriptional activity and DNA binding activity respectively.Results: EGCG could significantly increase Nmnat2 protein expression and enzyme activity in cultured neonatal rat cardiomyocytes stimulated with angiotensin II (Ang II) and heart tissues from rats subjected to abdominal aortic constriction. Nmnat2 knockdown by RNA interference attenuated the inhibitory effect of EGCG on cardiac hypertrophy. EGCG blocked NF-kappa B DNA binding activity induced by Ang II, which was dependent on Nmnat2 and the subsequent SIRT6 activation. Moreover the activation of PSMB5 (20S proteasome subunit beta-5, chymotrypsin-like) was required for EGCG-induced Nmnat2 protein expression. Additionally, we demonstrated that EGCG might interact with PSMB5 and inhibit the activation of the proteasome.Conclusions: These findings serve as the first evidence that the effect of EGCG against cardiac hypertrophy may be, at least partially, attributed to the modulation of the PSMB5/Nmnat2-dependent signalling pathway, suggesting the therapeutic potential of EGCG in the prevention and treatment of cardiac hypertrophy.