Involvement of Endoplasmic Reticulum Stress-Mediated Activation of C/EBP Homologous Protein in Aortic Regurgitation-Induced Cardiac Remodeling in Mice
Involvement of Endoplasmic Reticulum Stress-Mediated Activation of C/EBP Homologous Protein in Aortic Regurgitation-Induced Cardiac Remodeling in Mice
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内质网应激介导的 C/EBP 同源蛋白激活参与主动脉瓣反流诱导的小鼠心脏重塑
DOI：
10.1007/s12265-021-10162-4
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发表时间：
2021-08
影响因子：
3.4
通讯作者：
Zou Yunzeng
中科院分区：
文献类型：
--
作者：
Wang Xingxu;Wei Wei;Wu Jian;Kang Le;Wu Shuangquan;Li Jiming;Shen Yunli;You Jieyun;Ye Yong;Zhang Qi;Zou Yunzeng
主动脉瓣反流（AR）是一种容量超负荷性疾病，可导致偏心性左心室（LV）肥大并最终导致心力衰竭。目前还没有批准的药物用于治疗AR患者。内质网应激和内质网应激介导的细胞凋亡参与了许多心血管疾病，但它们是否也参与了AR诱导的心力衰竭仍然是一个谜。在这项研究中，我们发现ER应激激活的心肌样品与AR患者。通过诱导离心性心脏肥大和心力衰竭的独特小鼠AR模型，我们还发现心脏ER应激和细胞凋亡加剧，如Bcl-2/Bax比率降低和caspase-3切割增加所证明。然后，我们研究了参与ER启动的细胞凋亡的信号效应子，发现容量过载特异性激活C/EBP同源蛋白（CHOP），但不激活caspase-12或Jun N-末端激酶（JNK）。有趣的是，牛磺熊去氧胆酸（TUDCA），ER应激抑制剂，改善心脏功能，抑制ER应激，细胞凋亡和CHOP。此外，基因敲低CHOP抑制心脏Bcl-2/Bax比值降低和caspase-3激活，挽救心功能不全。总之，我们的研究结果表明，ER应激-CHOP信号通过促进心肌细胞凋亡参与了AR诱导的容量超负荷心肌肥大的发展，并为容量超负荷诱导的心力衰竭提供了一个以前未被认识的靶点。
Aortic regurgitation (AR) is a volume overload disease causing eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis is involved in many cardiovascular diseases, but whether they also participate in AR-induced heart failure is still elusive. In this study, we found ER stress activation in myocardial samples from patients with AR. With a unique murine model of AR which induced eccentric cardiac hypertrophy and heart failure, we also found aggravation of cardiac ER stress and apoptosis, as evidenced by a reduction of Bcl-2/Bax ratio and an increase of caspase-3 cleavage. We then examined the signaling effectors involved in ER-initiated apoptosis and found volume overload specifically activated C/EBP homologous protein (CHOP), but not caspase-12 or Jun N-terminal kinase (JNK). Interestingly, tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, improved cardiac function, and suppressed ER stress, apoptosis, and CHOP. Furthermore, genetic knockdown of CHOP inhibited cardiac Bcl-2/Bax ratio reduction and caspase-3 activation and rescued cardiac dysfunction. In summary, our findings suggest that ER stress-CHOP signaling is involved in the development of volume overload cardiac hypertrophy induced by AR through promoting cardiomyocytes apoptosis and provide a previously unrecognized target in heart failure induced by volume overload.
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DOI：
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发表时间：
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发表时间：
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影响因子：
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