Institute of Translational Medicine, Nanchang University, Nanchang, China.
School of Life Science, Nanchang University, Nanchang, China.
J Cell Mol Med. 2018 Jul;22(7):3638-3651. doi: 10.1111/jcmm.13645. Epub 2018 Apr 22.
We previously observed that disruption of FK506-binding protein 12.6 (FKBP12.6) gene resulted in cardiac hypertrophy in male mice. Studies showed that overexpression of FKBP12.6 attenuated thoracic aortic constriction (TAC)-induced cardiac hypertrophy in mice, whereas the adenovirus-mediated overexpression of FKBP12.6 induced hypertrophy and apoptosis in cultured neonatal cardiomyocytes, indicating that the role of FKBP12.6 in cardiac hypertrophy is still controversial. In this study, we aimed to investigate the roles and mechanisms of FKBP12.6 in angiotensin II (AngII)-induced cardiac hypertrophy using various transgenic mouse models in vivo and in vitro. FKBP12.6 knockout (FKBP12.6 ) mice and cardiac-specific FKBP12.6 overexpressing (FKBP12.6 TG) mice were infused with AngII (1500 ng/kg/min) for 14 days subcutaneously by implantation of an osmotic mini-pump. The results showed that FKBP12.6 deficiency aggravated AngII-induced cardiac hypertrophy, while cardiac-specific overexpression of FKBP12.6 prevented hearts from the hypertrophic response to AngII stimulation in mice. Consistent with the results in vivo, overexpression of FKBP12.6 in H9c2 cells significantly repressed the AngII-induced cardiomyocyte hypertrophy, seen as reductions in the cell sizes and the expressions of hypertrophic genes. Furthermore, we demonstrated that the protection of FKBP12.6 on AngII-induced cardiac hypertrophy was involved in reducing the concentration of intracellular Ca ([Ca ]i), in which the protein significantly inhibited the key Ca /calmodulin-dependent signalling pathways such as calcineurin/cardiac form of nuclear factor of activated T cells 4 (NFATc4), calmodulin kinaseII (CaMKII)/MEF-2, AKT/Glycogen synthase kinase 3β (GSK3β)/NFATc4 and AKT/mTOR signalling pathways. Our study demonstrated that FKBP12.6 protects heart from AngII-induced cardiac hypertrophy through inhibiting Ca /calmodulin-mediated signalling pathways.
我们之前观察到 FK506 结合蛋白 12.6（FKBP12.6）基因的破坏会导致雄性小鼠的心脏肥大。研究表明，FKBP12.6 的过表达减弱了小鼠胸主动脉缩窄（TAC）诱导的心脏肥大，而腺病毒介导的 FKBP12.6 过表达则在培养的新生心肌细胞中诱导肥大和凋亡，表明 FKBP12.6 在心脏肥大中的作用仍存在争议。在这项研究中，我们旨在使用体内和体外的各种转基因小鼠模型研究 FKBP12.6 在血管紧张素 II（AngII）诱导的心脏肥大中的作用和机制。FKBP12.6 敲除（FKBP12.6）小鼠和心脏特异性 FKBP12.6 过表达（FKBP12.6 TG）小鼠通过皮下植入渗透微型泵输注 AngII（1500ng/kg/min）14 天。结果表明，FKBP12.6 缺乏加重了 AngII 诱导的心脏肥大，而心脏特异性过表达 FKBP12.6 则防止了心脏对 AngII 刺激的肥大反应。与体内结果一致，FKBP12.6 在 H9c2 细胞中的过表达显著抑制了 AngII 诱导的心肌细胞肥大，表现为细胞体积减小和肥大基因的表达减少。此外，我们证明 FKBP12.6 对 AngII 诱导的心脏肥大的保护作用涉及降低细胞内 Ca（[Ca]i）浓度，其中该蛋白显著抑制了关键的 Ca/钙调蛋白依赖性信号通路，如钙调神经磷酸酶/活化 T 细胞核因子 4 的心脏形式（NFATc4）、钙调蛋白激酶 II（CaMKII）/肌细胞增强因子 2（MEF-2）、AKT/糖原合酶激酶 3β（GSK3β）/NFATc4 和 AKT/mTOR 信号通路。我们的研究表明，FKBP12.6 通过抑制 Ca/钙调蛋白介导的信号通路来保护心脏免受 AngII 诱导的心脏肥大。
