Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Transl Res. 2021 Jul;233:62-76. doi: 10.1016/j.trsl.2021.02.011. Epub 2021 Feb 27.
Activation of the innate immune system represents a vital step in inflammation during cardiac remodeling induced by the angiotensin II (Ang II). This study aimed to explore the role of Toll-like receptors 2 (TLR2) in Ang II-induced cardiac remodeling. We investigated the effect of TLR2 deficiency on Ang II-induced cardiac remodeling by utilizing TLR2 knockout mice, bone marrow transplantation models, and H9C2 cells. Though TLR2 deficiency had no effect on body weight change, cardiac Ang II content and blood pressure, it significantly ameliorated cardiac hypertrophy, fibrosis and inflammation, as well as improved heart function. Further bone marrow transplantation studies showed that TLR2-deficiency in cardiac cells but not bone marrow-derived cells prevented Ang II-induced cardiac remodeling and cardiac dysfunction. The underlying mechanism may involve increased TLR2-MyD88 interaction. Further in vitro studies in Ang II-treated H9C2 cells showed that TLR2 knockdown by siRNA significantly decreased Ang II-induced cell hypertrophy, fibrosis and inflammation. Moreover, Ang II significantly increased TLR2-MyD88 interaction in H9C2 cells in a TLR4-independent manner. TLR2 deficiency in cardiac cells prevents Ang II-induced cardiac remodeling, inflammation and dysfunction through reducing the formation of TLR2-MyD88 complexes. Inhibition of TLR2 pathway may be a therapeutic strategy of hypertensive heart failure.
先天免疫系统的激活是血管紧张素 II（Ang II）诱导的心脏重构过程中炎症发生的关键步骤。本研究旨在探讨 Toll 样受体 2（TLR2）在 Ang II 诱导的心脏重构中的作用。我们利用 TLR2 基因敲除小鼠、骨髓移植模型和 H9C2 细胞，研究了 TLR2 缺失对 Ang II 诱导的心脏重构的影响。虽然 TLR2 缺失对体重变化没有影响，也不影响心脏 Ang II 含量和血压，但它显著改善了心脏肥大、纤维化和炎症，并改善了心脏功能。进一步的骨髓移植研究表明，TLR2 在心细胞而非骨髓来源细胞中的缺失可预防 Ang II 诱导的心脏重构和心脏功能障碍。潜在的机制可能涉及 TLR2-MyD88 相互作用的增加。进一步在 Ang II 处理的 H9C2 细胞中的体外研究表明，siRNA 敲低 TLR2 显著降低了 Ang II 诱导的细胞肥大、纤维化和炎症。此外，Ang II 以 TLR4 非依赖性方式显著增加了 H9C2 细胞中 TLR2-MyD88 相互作用。TLR2 在心细胞中的缺失通过减少 TLR2-MyD88 复合物的形成，预防 Ang II 诱导的心脏重构、炎症和功能障碍。抑制 TLR2 途径可能是高血压性心力衰竭的一种治疗策略。
