Theranostics 2019; 9(22):6550-6567. doi:10.7150/thno.35218

Research Paper

Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction

Oi Kuan Choong1,2, Chen-Yun Chen2, Jianhua Zhang3, Jen-Hao Lin2, Po-Ju Lin2, Shu-Chian Ruan2, Timothy J. Kamp3, Patrick C.H. Hsieh1,2,3,4 ✉

1. Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
3. Department of Medicine and Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, WI, USA
4. Institute of Medical Genomics and Proteomics and Department of Surgery, National Taiwan University and Hospital, Taipei, Taiwan

Abstract

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.

Keywords: Long noncoding RNA, extracellular matrix, cardiac remodeling, fibrosis

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How to cite this article:
Choong OK, Chen CY, Zhang J, Lin JH, Lin PJ, Ruan SC, Kamp TJ, Hsieh PCH. Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction. Theranostics 2019; 9(22):6550-6567. doi:10.7150/thno.35218. Available from http://www.thno.org/v09p6550.htm