Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Oxid Med Cell Longev. 2022 Apr 26;2022:9469143. doi: 10.1155/2022/9469143. eCollection 2022.
Tumor necrosis factor--induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been reported to regulate inflammation and apoptosis. The role of TIPE2 in cardiovascular disease, especially cardiac hypertrophy, has not been elucidated. Thus, the aim of the present study was to explore the role of TIPE2 in cardiac hypertrophy.
Mice were subjected to aortic banding (AB) to induce an adverse hypertrophic model. To overexpress TIPE2, mice were injected with a lentiviral vector expressing TIPE2. Echocardiographic and hemodynamic analyses were used to evaluate cardiac function. Neonatal rat cardiomyocytes (NRCMs) and mouse peritoneal macrophages (MPMs) were isolated and stimulated with angiotensin II. NRCMs and MPM were also cocultured and stimulated with angiotensin II. Cells were transfected with Lenti-TIPE2 to overexpress TIPE2.
TIPE2 expression levels were downregulated in hypertrophic mouse hearts and in macrophages in heart tissue. TIPE2 overexpression attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, we found that TIPE2 overexpression in neonatal cardiomyocytes did not relieve the angiotensin II-induced hypertrophic response in vitro. Furthermore, TIPE2 overexpression downregulated TLR4 and NF-B signaling in macrophages but not in cardiomyocytes, which led to diminished inflammation in macrophages and consequently reduced the activation of hypertrophic Akt signaling in cardiomyocytes. TLR4 inhibition by TAK-242 did not enhance the antihypertrophic effect of TIPE2 overexpression.
The present study indicated that TIPE2 represses macrophage activation by targeting TLR4, subsequently inhibiting cardiac hypertrophy.
肿瘤坏死因子诱导蛋白 8 样蛋白 2（TIPE2）是一种新型的免疫调节蛋白，已被报道可调节炎症和细胞凋亡。TIPE2 在心血管疾病中的作用，特别是心肌肥厚，尚未阐明。因此，本研究旨在探讨 TIPE2 在心肌肥厚中的作用。
通过主动脉缩窄（AB）使小鼠产生不利的肥厚模型来使小鼠产生 TIPE2 过表达，向小鼠注射表达 TIPE2 的慢病毒载体。使用超声心动图和血流动力学分析来评估心脏功能。分离和刺激新生大鼠心肌细胞（NRCMs）和小鼠腹腔巨噬细胞（MPMs），用血管紧张素 II 刺激 NRCMs 和 MPMs 进行共培养。用 Lenti-TIPE2 转染细胞以过表达 TIPE2。
TIPE2 的表达水平在肥厚的小鼠心脏和心脏组织中的巨噬细胞中下调。TIPE2 过表达可减轻压力超负荷引起的心肌肥厚、纤维化和心功能障碍。此外，我们发现 TIPE2 在新生心肌细胞中的过表达不能缓解体外血管紧张素 II 引起的心肌肥厚反应。此外，TIPE2 过表达下调了巨噬细胞中的 TLR4 和 NF-B 信号，但在心肌细胞中没有下调，这导致巨噬细胞中的炎症减少，从而减少心肌细胞中 Akt 信号的激活。TLR4 抑制 TAK-242 并没有增强 TIPE2 过表达的抗肥厚作用。
本研究表明 TIPE2 通过靶向 TLR4 抑制巨噬细胞的激活，从而抑制心肌肥厚。
