Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction
Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction
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DOI：
10.7150/thno.35218
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Hsieh, Patrick C. H.
中科院分区：
文献类型：
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作者：
Choong, Oi Kuan;Chen, Chen-Yun;Hsieh, Patrick C. H.
理论基础：长非编码RNA(LncRNAs)已被认为是心脏发育和心脏发病机制中的关键新调节因子。LncRNA H19被认为是一个胎儿基因，但它只在成年时丰富地存在于心脏和骨骼肌中，并在进化上在人类和小鼠中保守。据报道，它与冠状动脉疾病的风险有显著的相关性。方法：采用冠状动脉左前降支结扎术后功能丧失和功能恢复的小鼠模型，评价H19在体内的功能。在机制研究方面，在体外模拟心肌缺血损伤的模型中施加低氧条件。用RNA免疫沉淀法分离染色质，以确定lncRNA H19的相互作用蛋白。结果：小鼠模型术后第4天，梗死区内lncRNA H19表达显著上调。H19在小鼠心脏中的异位表达导致严重的心脏扩张和纤维化。细胞外基质(ECM)基因表达明显上调。而CRISPR-CAS9基因消融H19可改善心肌梗死后心脏重构，降低ECM基因的表达。通过RNA纯化的染色质分离(CHIRP)，我们鉴定了胶原1A1的抑制因子Y盒结合蛋白(YB)-1是H19的相互作用蛋白。结论：LncRNA H19及其相互作用蛋白YB-1在心脏重塑过程中对ECM的调控起重要作用。
Rationale: Long non-coding RNA (lncRNAs) has been identified as a pivotal novel regulators in cardiac development as well as cardiac pathogenesis. lncRNA H19 is known as a fetal gene but it is exclusively abundant in the heart and skeletal muscles in adulthood, and is evolutionarily conserved in humans and mice. It has been reported to possess a significant correlation with the risk of coronary artery diseases. However, the function of H19 is not well characterized in heart.Methods: Loss-of-function and gain-of-function mouse models with left anterior descending coronary artery-ligation surgery were utilized to evaluate the functionality of H19 in vivo. For mechanistic studies, hypoxia condition were exerted in in vitro models to mimic cardiac ischemic injury. Chromatin isolation by RNA immunoprecipitation (ChIRP) was performed to reveal the interacting protein of lncRNA H19.Results: lncRNA H19 was significantly upregulated in the infarct area post-surgery day 4 in mouse model. Ectopic expression of H19 in the mouse heart resulted in severe cardiac dilation and fibrosis. Several extracellular matrix (ECM) genes were significantly upregulated. While genetic ablation of H19 by CRISPR-Cas9 ameliorated post-MI cardiac remodeling with reduced expression in ECM genes. Through chromatin isolation by RNA purification (ChIRP), we identified Y-box-binding protein (YB)-1, a suppressor of Collagen 1A1, as an interacting protein of H19. Furthermore, H19 acted to antagonize YB-1 through direct interaction under hypoxia, which resulted in de-repression of Collagen 1A1 expression and cardiac fibrosis.Conclusions: Together these results demonstrate that lncRNA H19 and its interacting protein YB-1 are crucial for ECM regulation during cardiac remodeling.