Cardiac-specific Trim44 knockout in rat attenuates isoproterenol-induced cardiac remodeling via inhibition of AKT/mTOR pathway.
Cardiac-specific Trim44 knockout in rat attenuates isoproterenol-induced cardiac remodeling via inhibition of AKT/mTOR pathway.
复制标题
大鼠心脏特异性 Trim44 敲除通过抑制 AKT/mTOR 通路减弱异丙肾上腺素诱导的心脏重塑
DOI：
10.1242/dmm.049444
复制
发表时间：
2023-05-01
影响因子：
4.3
通讯作者：
Lu, Dan
中科院分区：
文献类型：
--
作者：
Jiang, Xiao-Yu;Guan, Fei-Fei;Ma, Jia-Xin;Dong, Wei;Qi, Xiao-Long;Zhang, Xu;Chen, Wei;Gao, Shan;Gao, Xiang;Pan, Shuo;Wang, Ji-Zheng;Ma, Yuan-Wu;Zhang, Lian-Feng;Lu, Dan
摘要当病理性肥厚进展为心力衰竭(HF)时，预后往往很差。因此，寻找新的、有效的干预目标至关重要。在这里，心肌特异性Trim44基因敲除大鼠是使用CRISPR-Cas9技术产生的。心脏表型观察显示，Trim44基因敲除影响基线时的心脏形态。Trim44缺陷大鼠对异丙肾上腺素(ISO)刺激引起的心脏病理改变表现出抵抗，包括通过形态和功能观察改善心脏重塑和功能障碍，减少心肌纤维化和心脏应激分子标记物的表达。此外，与体内和体外生长和肥大发育相关的信号转导验证表明，Trim44缺陷抑制了参与心肌肥大的信号通路的激活，特别是对病理性应激的反应。综上所述，本研究表明Trim44基因敲除可通过阻断AKT/MTOR/GSK3β/p70S6K信号通路而减轻异丙肾上腺素诱导的病理性心脏重构。这是第一个证明Trim44在心脏基线和病理性应激状态下的功能和重要性的研究。TRIM44可能成为预防心肌肥厚和心力衰竭的新治疗靶点。
ABSTRACT When pathological hypertrophy progresses to heart failure (HF), the prognosis is often very poor. Therefore, it is crucial to find new and effective intervention targets. Here, myocardium-specific Trim44 knockout rats were generated using CRISPR-Cas9 technology. Cardiac phenotypic observations revealed that Trim44 knockout affected cardiac morphology at baseline. Rats with Trim44 deficiency exhibited resistance to cardiac pathological changes in response to stimulation via isoproterenol (ISO) treatment, including improvement of cardiac remodeling and dysfunction by morphological and functional observations, reduced myocardial fibrosis and reduced expression of molecular markers of cardiac stress. Furthermore, signal transduction validation associated with growth and hypertrophy development in vivo and in vitro demonstrated that Trim44 deficiency inhibited the activation of signaling pathways involved in myocardial hypertrophy, especially response to pathological stress. In conclusion, the present study indicates that Trim44 knockout attenuates ISO-induced pathological cardiac remodeling through blocking the AKT/mTOR/GSK3β/P70S6K signaling pathway. This is the first study to demonstrate the function and importance of Trim44 in the heart at baseline and under pathological stress. Trim44 could be a novel therapeutic target for prevention of cardiac hypertrophy and HF.
登录
查看更多内容
影响因子：
5
作者：
Heliste, Juho;Chheda, Himanshu;Aittokallio, Tero
通讯作者：
Aittokallio, Tero
影响因子：
5.6
作者：
Kemi, Ole Johan;Ceci, Marcello;Ellingsen, Oyvind
通讯作者：
Ellingsen, Oyvind
DOI：
10.1016/s0169-328x(00)00281-3
发表时间：
2001-01-31
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Boutou, E;Matsas, R;Mamalaki, A
通讯作者：
Mamalaki, A
LKB1IP 通过靶向 PTEN/Akt 信号通路促进病理性心脏肥大。
影响因子：
5.3
作者：
Tian M;Jiang X;Li X;Yang J;Zhang C;Zhang W
通讯作者：
Zhang W
影响因子：
11.4
作者：
Chen Z;Lin TC;Bi X;Lu G;Dawson BC;Miranda R;Medeiros LJ;McNiece I;McCarty N
通讯作者：
McCarty N