Research ArticleCARDIAC FIBROSIS

The long noncoding RNA Wisper controls cardiac fibrosis and remodeling

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Science Translational Medicine  21 Jun 2017:
Vol. 9, Issue 395, eaai9118
DOI: 10.1126/scitranslmed.aai9118

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“Lnc”ing fibroblasts to cardiac fibrosis

Therapies for myocardial infarction or injury typically focus on cardiomyocytes, the contractile cells of the heart. However, cardiac fibroblasts deposit extracellular matrix to compensate for reduced cardiac function, playing a key role in the pathogenesis of heart failure. Micheletti et al. identified a super-enhancer–associated long noncoding RNA, Wisper, enriched in cardiac fibroblasts and up-regulated in infarcted mouse heart tissue. Treating mice with antisense oligonucleotides to Wisper after infarction, when fibrosis was already initiated, reduced the expression of collagens and cardiac stress markers, decreased tissue remodeling, and improved cardiac function and survival. WISPER expression was increased in human tissue samples from patients with aortic stenosis and correlated with collagen volume fraction and severity of fibrosis. Fibroblast-specific long noncoding RNAs may be useful targets for fibrosis therapies.

Abstract

Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, we identified Wisper (Wisp2 super-enhancer–associated RNA) as a cardiac fibroblast–enriched lncRNA that regulates cardiac fibrosis after injury. Wisper expression was correlated with cardiac fibrosis both in a murine model of myocardial infarction (MI) and in heart tissue from human patients suffering from aortic stenosis. Loss-of-function approaches in vitro using modified antisense oligonucleotides (ASOs) demonstrated that Wisper is a specific regulator of cardiac fibroblast proliferation, migration, and survival. Accordingly, ASO-mediated silencing of Wisper in vivo attenuated MI-induced fibrosis and cardiac dysfunction. Functionally, Wisper regulates cardiac fibroblast gene expression programs critical for cell identity, extracellular matrix deposition, proliferation, and survival. In addition, its association with TIA1-related protein allows it to control the expression of a profibrotic form of lysyl hydroxylase 2, implicated in collagen cross-linking and stabilization of the matrix. Together, our findings identify Wisper as a cardiac fibroblast–enriched super-enhancer–associated lncRNA that represents an attractive therapeutic target to reduce the pathological development of cardiac fibrosis in response to MI and prevent adverse remodeling in the damaged heart.

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