C1QTNF1 attenuates angiotensin II-induced cardiac hypertrophy via activation of the AMPKa pathway.
C1QTNF1 attenuates angiotensin II-induced cardiac hypertrophy via activation of the AMPKa pathway.
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C1QTNF1 通过激活 AMPKa 通路减轻血管紧张素 II 诱导的心脏肥大
DOI：
10.1016/j.freeradbiomed.2018.05.004
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发表时间：
2018
影响因子：
7.4
通讯作者：
Zhang Yanzhou
中科院分区：
文献类型：
--
作者：
Wu Leiming;Gao Lu;Zhang Dianhong;Yao Rui;Huang Zhen;Du Binbin;Wang Zheng;Xiao Lili;Li Pengcheng;Li Yapeng;Liang Cui;Zhang Yanzhou
补体C1 q肿瘤坏死因子相关蛋白（C1 QTNFs）对心血管系统有多种生物学影响。C1 QTNF 1是CTRP超家族的成员。C1 QTNF 1在心肌中表达，然而，其在心肌细胞中的功能尚未被investigated.ObjectiveC1QTNF1在血管紧张素II（Ang II）诱导的心肌肥厚中的作用进行了系统的研究方法和结果C1 QTNF 1基因敲除小鼠的目的是确定C1 QTNF 1在成人心脏心肌肥厚的作用。实验数据显示，C1 QTNF 1在心脏肥大过程中上调，这是由活性氧增加触发的。C1 QTNF 1缺乏加速了Ang II诱导的心脏肥大小鼠模型中的心脏肥大、纤维化、炎症反应和氧化应激，并恶化了心功能障碍。我们使用重组人C1 QTNF 1球状结构域和C1 QTNF 1 siRNA鉴定了C1 QTNF 1作为Ang II刺激的新生大鼠心肌细胞中心肌细胞肥大的负调节因子。注射重组人C1 QTNF 1球状结构域也抑制了体内Ang II诱导的心脏肥大反应。C1 QTNF 1的抗肥大作用依赖于AMPKa激活，其抑制mTOR P70 S6 K磷酸化。AMPKa抑制剂在体内和体外均消除了重组人C1 QTNF 1球状结构域的抗肥大作用。此外，C1 QTNF 1介导的AMPKa激活触发的抑制PDE 1 -4，随后激活cAMP/PKA/LKB 1 pathway.ConclusionOur结果表明，C1 QTNF 1改善心功能，抑制心肌肥厚和纤维化，通过增加和激活AMPKa，表明C1 QTNF 1可能是一个治疗心肌肥厚和心力衰竭的靶点。
RationaleComplement C1q tumor necrosis factor related proteins (C1QTNFs) have been reported to have diverse biological influence on the cardiovascular system. C1QTNF1 is a member of the CTRP superfamily. C1QTNF1 is expressed in the myocardium; however, its function in myocytes has not yet been investigated.ObjectiveTo systematically investigate the roles of C1QTNF1 in angiotensin II (Ang II)-induced cardiac hypertrophy.Methods and resultsC1QTNF1 knock-out mice were used with the aim of determining the role of C1QTNF1 in cardiac hypertrophy in the adult heart. Data from experiments showed that C1QTNF1 was up-regulated during cardiac hypertrophic processes, which were triggered by increased reactive oxygen species. C1QTNF1 deficiency accelerated cardiac hypertrophy, fibrosis, inflammation responses, and oxidative stress with deteriorating cardiac dysfunction in the Ang II-induced cardiac hypertrophy mouse model. We identified C1QTNF1 as a negative regulator of cardiomyocyte hypertrophy in Ang II-stimulated neonatal rat cardiomyocytes using the recombinant human globular domain of C1QTNF1 and C1QTNF1 siRNA. Injection of the recombinant human globular domain of C1QTNF1 also suppressed the Ang II-induced cardiac hypertrophic response in vivo. The anti-hypertrophic effects of C1QTNF1 rely on AMPKa activation, which inhibits mTOR P70S6K phosphorylation. An AMPKa inhibitor abrogated the anti-hypertrophic effects of the recombinant human globular domain of C1QTNF1 both in vivo and vitro. Moreover, C1QTNF1-mediated AMPKa activation was triggered by the inhibition of PDE1-4, which subsequently activated the cAMP/PKA/LKB1 pathway.ConclusionOur results demonstrated that C1QTNF1 improves cardiac function and inhibits cardiac hypertrophy and fibrosis by increasing and activating AMPKa, suggesting that C1QTNF1 could be a therapeutic target for cardiac hypertrophy and heart failure.