Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center For Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 211166, China.
Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Basic Res Cardiol. 2020 Feb 1;115(2):19. doi: 10.1007/s00395-020-0779-1.
Activation of TLRs mediated the NF-κB signaling pathway plays an important pathophysiological role in cardiac hypertrophy. Triad3A, a ubiquitin E3 ligase, has been reported to negatively regulate NF-κB activation pathway via promoting ubiquitination and degradation of TLR4 and TLR9 in innate immune cells. The role of Triad3A in cardiac hypertrophic development remains unknown. The present study investigated whether there is a link between Triad3A and TLR4 and TLR9 in pressure overload induced cardiac hypertrophy. We observed that Triad3A levels were markedly reduced following transverse aortic constriction (TAC) induced cardiac hypertrophy. Similarly, stimulation of neonatal rat cardiac myocytes (NRCMs) with angiotensin-II (Ang II) significantly decreased Triad3A expression. To determine the role of Triad3A in TAC-induced cardiac hypertrophy, we transduced the myocardium with adenovirus expressing Triad3A followed by induction of TAC. We observed that increased expression of Triad3A significantly attenuated cardiac hypertrophy and improved cardiac function. To investigate the mechanisms by which Triad3A attenuated cardiac hypertrophy, we examined the Triad3A E3 ubiquitination on TLR4 and TLR9. We found that Triad3A promoted TLR4 and TLR9 degradation through ubiquitination. Triad3A mediated TLR4 and TLR9 degradation resulted in suppression of NF-κB activation. Our data suggest that Triad3A plays a protective role in the development of cardiac hypertrophy, at least through catalyzing ubiquitination-mediated degradation of TLR4 and TLR9, thus negatively regulating NF-κB activation.
TLRs 介导的 NF-κB 信号通路的激活在心脏肥大的病理生理过程中发挥着重要作用。泛素 E3 连接酶 Triad3A 已被报道通过促进先天免疫细胞中 TLR4 和 TLR9 的泛素化和降解来负调控 NF-κB 激活途径。Triad3A 在心脏肥大发展中的作用尚不清楚。本研究探讨了 Triad3A 与 TLR4 和 TLR9 之间在压力超负荷诱导的心脏肥大中的关系。我们观察到，在主动脉缩窄（TAC）诱导的心脏肥大后，Triad3A 水平明显降低。同样，血管紧张素-II（Ang II）刺激新生大鼠心肌细胞（NRCMs）也显著降低了 Triad3A 的表达。为了确定 Triad3A 在 TAC 诱导的心脏肥大中的作用，我们用表达 Triad3A 的腺病毒转导心肌，然后进行 TAC 诱导。我们观察到，Triad3A 的表达增加显著减轻了心脏肥大并改善了心脏功能。为了研究 Triad3A 减轻心脏肥大的机制，我们检查了 Triad3A 对 TLR4 和 TLR9 的 E3 泛素化作用。我们发现 Triad3A 通过泛素化促进 TLR4 和 TLR9 的降解。Triad3A 介导的 TLR4 和 TLR9 降解导致 NF-κB 激活受到抑制。我们的数据表明，Triad3A 在心脏肥大的发展中发挥保护作用，至少通过催化 TLR4 和 TLR9 的泛素化介导的降解，从而负调控 NF-κB 的激活。
