CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress.
CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress.
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DOI：
10.1161/circresaha.119.315881
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发表时间：
2020-08-14
影响因子：
20.1
通讯作者：
Rosenzweig A
中科院分区：
文献类型：
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作者：
Lerchenmüller C;Rabolli CP;Yeri A;Kitchen R;Salvador AM;Liu LX;Ziegler O;Danielson K;Platt C;Shah R;Damilano F;Kundu P;Riechert E;Katus HA;Saffitz JE;Keshishian H;Carr SA;Bezzerides VJ;Das S;Rosenzweig A
心脏 CITED4 由运动诱导，足以引起生理性肥大并减轻缺血性损伤后不利的心室重塑。然而，内源性 CITED4 在生理或病理应激反应中的作用尚不清楚。研究 CITED4 在小鼠运动和压力超负荷模型中的作用。我们培育了心肌细胞特异性 CITED4 基因敲除小鼠 (C4KO)，并对它们进行强化游泳运动方案以及主动脉横缩术 (TAC)。对 mRNA 和 miRNA 表达进行了超声心动图、蛋白质印迹、qPCR、免疫组织化学、免疫荧光以及转录谱分析。在体外研究了细胞串扰。心肌细胞中 CITED4 的缺失并不影响年轻成年小鼠的基线心脏大小或功能。 C4KO 小鼠因运动而出现轻度心脏功能障碍和扩张。 TAC 后，C4KO 出现严重心力衰竭，伴有左心室扩张、心肌细胞生长受损、哺乳动物雷帕霉素靶点 (mTOR) 活性降低，以及适应不良的心脏重塑（凋亡、自噬增加和线粒体信号传导受损）。 TAC 后 C4KO 心脏的间质纤维化显着增加。 RNAseq 揭示了促纤维化 miRNA 网络的诱导。 TAC 后 C4KO 心脏中 miR30d 减少，并介导心肌细胞和成纤维细胞之间的串扰以调节纤维化。 miR30d 抑制足以增加 TAC 后的心脏功能障碍和纤维化。 CITED4 通过调节 mTOR 活性和介导心肌细胞与成纤维细胞串扰的 miRNA 网络来防止病理性心脏重塑。我们的研究结果强调了 CITED4 对生理和病理刺激做出反应的重要性。
Cardiac CITED4 is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown. To investigate the role of CITED4 in murine models of exercise and pressure overload. We generated cardiomyocyte-specific CITED4 knockout mice (C4KO) and subjected them to an intensive swim exercise protocol as well as transverse aortic constriction (TAC). Echocardiography, western blotting, qPCR, immunohistochemistry, immunofluorescence, and transcriptional profiling for mRNA and miRNA expression were performed. Cellular crosstalk was investigated in vitro. CITED4 deletion in cardiomyocytes did not affect baseline cardiac size or function in young adult mice. C4KO mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, C4KOs developed severe heart failure with left ventricular dilation, impaired cardiomyocyte growth accompanied by reduced mammalian target of rapamycin (mTOR) activity and maladaptive cardiac remodeling with increased apoptosis, autophagy, and impaired mitochondrial signaling. Interstitial fibrosis was markedly increased in C4KO hearts after TAC. RNAseq revealed induction of a pro-fibrotic miRNA network. miR30d was decreased in C4KO hearts after TAC and mediated crosstalk between cardiomyocytes and fibroblasts to modulate fibrosis. miR30d inhibition was sufficient to increase cardiac dysfunction and fibrosis after TAC. CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk. Our findings highlight the importance of CITED4 in response to both physiological and pathological stimuli.