Forkhead box O6 (FoxO6) promotes cardiac pathological remodeling and dysfunction by activating Kif15-TGF-β1 under aggravated afterload.
Forkhead box O6 (FoxO6) promotes cardiac pathological remodeling and dysfunction by activating Kif15-TGF-β1 under aggravated afterload.
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作者：
Zhang, Bing;Shi, Lei;Tan, Yanzhen;Zhou, Yenong;Cui, Jun;Song, Yujie;Liu, Yingying;Zhang, Miao;Duan, Weixun;Jin, Zhenxiao;Liu, Jincheng;Yi, Dinghua;Sun, Yang;Yi, Wei
病理性心肌肥大表现出复杂和异常的基因表达模式，并进展为心力衰竭。叉头盒蛋白O 6（FoxO 6）是一种参与多种生物学过程的关键转录因子。本研究旨在探讨FoxO 6在心肌肥厚中的作用。建立了三组小鼠：野生型、FoxO 6敲除和FoxO 6过表达。小鼠每天接受血管紧张素II（Ang-II）或生理盐水给药4周，之后检查心脏肥大，纤维化和功能。在Ang-II处理的小鼠中观察到FoxO 6的心脏表达升高。FoxO 6缺乏减弱收缩功能障碍和心脏重塑，包括心肌细胞肥大和成纤维细胞增殖和分化。相反，FoxO 6过表达加重心肌病和心功能不全。进一步的研究确定驱动蛋白家族成员15（Kif 15）为FoxO 6的下游分子。Kif 15抑制减弱了FoxO 6过表达的加重作用。在体外，FoxO 6过表达增加了心肌细胞中Kif 15的表达，并提高了成纤维细胞生长培养基中转化生长因子-β1（TGF-β1）的浓度，表现出增殖和分化的增加，而FoxO 6敲低则减弱了这种作用。心脏源性FoxO 6主要通过激活Kif 15/TGF-β1轴促进由加重后负荷诱导的病理性心脏重塑。这一结果进一步补充了心脏中不同细胞之间的通讯机制，为心力衰竭提供了新的治疗靶点。压力超负荷是以左室肥厚和纤维化为特征的高血压心脏重构的关键促进因素。心脏纤维化的特征在于可以进展为心力衰竭的异常基因表达模式，并且被鉴定为心力衰竭的重要治疗靶点。转录因子FoxO 6参与许多生物过程。FoxO 6在心脏病中的调节作用仍不清楚。这项研究首次阐明了。FoxO 6是一种重要的转录因子，与心脏疾病的进展密切相关。FoxO 6通过在压力超负荷下激活心肌细胞分泌Kif 15和TGF-β1，促进成纤维细胞增殖和分化，从而促进病理性心脏纤维化和左心室收缩功能障碍。FoxO 6表达敲除导致抗纤维化作用并保护心脏功能。
Pathological cardiac hypertrophy exhibits complex and abnormal gene expression patterns and progresses to heart failure. Forkhead box protein O6 (FoxO6) is a key transcription factor involved in many biological processes. This study aimed to explore the role of FoxO6 in cardiac hypertrophy. Three groups of mice were established: wild‐type, FoxO6 knockout, and FoxO6‐overexpressing. The mice received daily administration of angiotensin‐II (Ang‐II) or saline for 4 weeks, after which they were examined for cardiac hypertrophy, fibrosis, and function. Elevated cardiac expression of FoxO6 was observed in Ang‐II‐treated mice. FoxO6 deficiency attenuated contractile dysfunction and cardiac remodeling, including cardiomyocyte hypertrophy and fibroblast proliferation and differentiation. Conversely, FoxO6 overexpression aggravated the cardiomyopathy and heart dysfunction. Further studies identified kinesin family member 15 (Kif15) as downstream molecule of FoxO6. Kif15 inhibition attenuated the aggravating effect of FoxO6 overexpression. In vitro, FoxO6 overexpression increased Kif15 expression in cardiomyocytes and elevated the concentration of transforming growth factor‐β1 (TGF‐β1) in the medium where fibroblasts were grown, exhibiting increased proliferation and differentiation, while FoxO6 knockdown attenuated this effect. Cardiac‐derived FoxO6 promoted pathological cardiac remodeling induced by aggravated afterload largely by activating the Kif15/TGF‐β1 axis. This result further complements the mechanisms of communication among different cells in the heart, providing novel therapeutic targets for heart failure. Pressure overload is a key promoter of hypertensive cardiac remodeling characterized by left ventricular hypertrophy and fibrosis. Cardiac fibrosis is characterized by abnormal gene expression patterns that can progress to heart failure and is identified as a vital therapeutic target for heart failure. The transcription factor FoxO6 is involved in many biological processes. The regulatory role of FoxO6 in cardiac diseases remains unclear. This study elucidated for the first time that. FoxO6 is an essential transcription factor that shows a strong association with the progression of cardiac disease. FoxO6 promotes pathological cardiac fibrosis and left ventricular contractile dysfunction by activating Kif15 and TGF‐β1 secretion in cardiomyocytes under pressure overload, which facilitates the proliferation and differentiation of fibroblasts. FoxO6 expression knockout leads to anti‐fibrosis effect and conserves cardiac function.
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影响因子：
37.8
作者：
Park S;Ranjbarvaziri S;Lay FD;Zhao P;Miller MJ;Dhaliwal JS;Huertas-Vazquez A;Wu X;Qiao R;Soffer JM;Rau C;Wang Y;Mikkola HKA;Lusis AJ;Ardehali R
通讯作者：
Ardehali R
影响因子：
5
作者：
Lighthouse JK;Small EM
通讯作者：
Small EM
影响因子：
4
作者：
Chung SY;Huang WC;Su CW;Lee KW;Chi HC;Lin CT;Chen ST;Huang KM;Tsai MS;Yu HP;Chen SL
通讯作者：
Chen SL
影响因子：
8.3
作者：
Bragazzi, Nicola Luigi;Zhong, Wen;Dai, Haijiang
通讯作者：
Dai, Haijiang
多能干细胞衍生的心肌细胞的旁分泌作用损伤心肌。
影响因子：
20.1
作者：
Tachibana A;Santoso MR;Mahmoudi M;Shukla P;Wang L;Bennett M;Goldstone AB;Wang M;Fukushi M;Ebert AD;Woo YJ;Rulifson E;Yang PC
通讯作者：
Yang PC