Department of Cardiology, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, Zhengzhou, China.
Department of Hepatobiliary Surgery, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, Zhengzhou, China.
Acta Physiol (Oxf). 2020 Nov;230(3):e13537. doi: 10.1111/apha.13537. Epub 2020 Jul 30.
The imbalance of T helper (Th) 17/T regulatory (Treg) is involved in chronic heart failure (HF). The enzyme lysyl oxidase (LOX) contributes to myocardial fibrosis. This study was designed to decipher the regulatory mechanism of Th17/Treg on LOX expression and to validate whether Th17/Treg imbalance regulates myocardial fibrosis by modulating LOX expression.
Human cardiac fibroblasts (HCFs) were treated with angiotensin II (Ang II) and co-cultured with Th17 cells and Tregs which were polarized from control naïve CD4 T cells. Th17 cells and Tregs were adoptively transferred into abdominal aortic coarctation-induced chronic HF rats to investigate the efficacy of Th17 and Treg infusions on myocardial fibrosis and HF.
Th17/Treg imbalance (increased Th17 cells and decreased Tregs) was observed in HF patients. Th17 cells/Tregs aggravated/attenuated Ang II-induced upregulation of LOX and fibrosis-related indicators (MMP-2/9 and collagen I/III) in HCFs in vitro and abdominal aortic coarctation-induced myocardial fibrosis and HF in rats, by promoting/inhibiting LOX expression. Mechanistically, Th17 cells promoted LOX expression by activating the IL-17/ERK1/2-AP-1 pathway, while Tregs inhibited LOX expression by activating the IL-10/JAK1-STAT3 pathway.
Increased Th17 cells and decreased Tregs aggravate myocardial fibrosis and HF by inducing LOX expression.
辅助性 T 细胞 17（Th17）/调节性 T 细胞（Treg）失衡参与慢性心力衰竭（HF）的发生。赖氨酰氧化酶（LOX）促进心肌纤维化。本研究旨在解析 Th17/Treg 对 LOX 表达的调控机制，并验证 Th17/Treg 失衡是否通过调节 LOX 表达来调节心肌纤维化。
用血管紧张素 II（Ang II）处理人心房成纤维细胞（HCFs），并与从对照幼稚 CD4 T 细胞极化而来的 Th17 细胞和 Treg 共培养。将 Th17 细胞和 Treg 过继转移到腹主动脉缩窄诱导的慢性 HF 大鼠中，以研究 Th17 和 Treg 输注对心肌纤维化和 HF 的疗效。
HF 患者存在 Th17/Treg 失衡（Th17 细胞增加，Treg 细胞减少）。Th17 细胞/Tregs 在体外加重/减轻 Ang II 诱导的 HCFs 中 LOX 和纤维化相关指标（MMP-2/9 和胶原 I/III）的上调，并在腹主动脉缩窄诱导的心肌纤维化和 HF 大鼠中加重/减轻心肌纤维化和 HF，通过促进/抑制 LOX 表达。机制上，Th17 细胞通过激活 IL-17/ERK1/2-AP-1 通路促进 LOX 表达，而 Treg 细胞通过激活 IL-10/JAK1-STAT3 通路抑制 LOX 表达。
Th17 细胞增加和 Treg 细胞减少通过诱导 LOX 表达加重心肌纤维化和 HF。
