Long Noncoding RNA Facilitated Gene Therapy Reduces Atherosclerosis in a Murine Model of Familial Hypercholesterolemia

Tontonoz, Peter; Wu, Xiaohui; Jones, Michael Owen; Zhang, Zhengyi; Salisbury, David; Sallam, Tamer

doi:10.1161/circulationaha.117.029002

Cited by 48 publications

(34 citation statements)

References 5 publications

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“…Since LeXis has been previously described to maintain hepatic sterol content and levels of serum cholesterol ( 56 ), the adenovirus-mediated LeXis overexpression in the liver was specifically designed using a thyroxine-binding globulin promoter. In line with their previous findings, LeXis overexpression reduced total serum cholesterol levels ( 55 ). This study raises the possibility for long-term lncRNA therapy in mice.…”

Section: Chronic Inflammationsupporting

confidence: 91%

“…al. demonstrated that in vivo delivery of the liver-expressed liver X receptor-induced lncRNA ( LeXis ) reduced aortic lesion size by Oil-red O staining ( 55 ). Since LeXis has been previously described to maintain hepatic sterol content and levels of serum cholesterol ( 56 ), the adenovirus-mediated LeXis overexpression in the liver was specifically designed using a thyroxine-binding globulin promoter.…”

Section: Chronic Inflammationmentioning

confidence: 99%

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Long Non-Coding RNAs in Vascular Inflammation

Haemmig

Simion

Feinberg

2018

Front. Cardiovasc. Med.

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Less than 2% of the genome encodes for proteins. Accumulating studies have revealed a diverse set of RNAs derived from the non-coding genome. Among them, long non-coding RNAs (lncRNAs) have garnered widespread attention over recent years as emerging regulators of diverse biological processes including in cardiovascular disease (CVD). However, our knowledge of their mechanisms by which they control CVD-related gene expression and cell signaling pathways is still limited. Furthermore, only a handful of lncRNAs has been functionally evaluated in the context of vascular inflammation, an important process that underlies both acute and chronic disease states. Because some lncRNAs may be expressed in cell- and tissue-specific expression patterns, these non-coding RNAs hold great promise as novel biomarkers and as therapeutic targets in health and disease. Herein, we review those lncRNAs implicated in pro- and anti-inflammatory processes of acute and chronic vascular inflammation. An improved understanding of lncRNAs in vascular inflammation may provide new pathophysiological insights in CVD and opportunities for the generation of a new class of RNA-based biomarkers and therapeutic targets.

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Section: Chronic Inflammationsupporting

confidence: 91%

Section: Chronic Inflammationmentioning

confidence: 99%

Long Non-Coding RNAs in Vascular Inflammation

Haemmig

Simion

Feinberg

2018

Front. Cardiovasc. Med.

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“…LeXis reduces cholesterol synthesis by interacting with and affecting the DNA interactions of RALY, a heterogeneous ribonucleoprotein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the mouse liver [103]. Notably, a gene therapy utilizing AAV8.hTBG.LeXis significantly reduced atherosclerotic burden in Ldlr −/− mice [104].…”

Section: Lncrnas In Lipid Metabolismmentioning

confidence: 99%

Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases

Yeh

Chang

et al. 2020

J Biomed Sci

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With the advances in deep sequencing-based transcriptome profiling technology, it is now known that human genome is transcribed more pervasively than previously thought. Up to 90% of the human DNA is transcribed, and a large proportion of the human genome is transcribed as long noncoding RNAs (lncRNAs), a heterogenous group of non-coding transcripts longer than 200 nucleotides. Emerging evidence suggests that lncRNAs are functional and contribute to the complex regulatory networks involved in cardiovascular development and diseases. In this article, we will review recent evidence on the roles of lncRNAs in the biological processes of cardiovascular development and disorders. The potential applications of lncRNAs as biomarkers and targets for therapeutics are also discussed.

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“…LeXis-Raly interaction prevented Raly-mediated recruitment of RNA polymerase II to the promoters of cholesterol biosynthesis genes, as Srebf2, Hmgcr, Cyp51 , and Fdps [31 ■■ ]. To test whether this decoying function of LeXis could be harnessed therapeutically, the investigators used an adeno-associated virus (AAV8)-based gene therapy approach currently in phase II clinical trials [32]. AAV8-mediated delivery of LeXis to Ldlr −/− mice prior to feeding mice an atherogenic western diet for 15 weeks reduced the expression of Srebf2 and its target genes in the liver, and caused a sustained reduction of serum cholesterol and triglyceride levels compared to control AAV8 treated mice.…”

Section: Long Noncoding Rnas Regulating the Sterol Regulatory Elementmentioning

confidence: 99%

Long noncoding RNAs in lipid metabolism

Solingen

Scacalossi

Moore

2018

Current Opinion in Lipidology

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Purpose of review Noncoding RNAs have emerged as important regulators of cellular and systemic lipid metabolism. In particular, the enigmatic class of long noncoding RNAs have been shown to play multifaceted roles in controlling transcriptional and posttranscriptional gene regulation. In this review, we discuss recent advances, current challenges and future opportunities in understanding the roles of lncRNAs in the regulation of lipid metabolism during health and disease. Recent findings Despite comprising the majority of the transcriptionally active regions of the human genome, lncRNA functions remain poorly understood, with fewer than 1% of human lncRNAs functionally characterized. Broadly defined as nonprotein coding transcripts greater than 200 nucleotides in length, lncRNAs execute their functions by forming RNA–DNA, RNA–protein, and RNA–RNA interactions that regulate gene expression through diverse mechanisms, including epigenetic remodeling of chromatin, transcriptional activation or repression, posttranscriptional regulation of mRNA, and modulation of protein activity. It is now recognized that in lipid metabolism, just as in other areas of biology, lncRNAs operate to regulate the expression of individual genes and gene networks at multiple different levels. Summary The complexity revealed by recent studies showing how lncRNAs can alter systemic and cell-type-specific cholesterol and triglyceride metabolism make it clear that we have entered a new frontier for discovery that is both daunting and exciting.

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Long Noncoding RNA Facilitated Gene Therapy Reduces Atherosclerosis in a Murine Model of Familial Hypercholesterolemia

Cited by 48 publications

References 5 publications

Long Non-Coding RNAs in Vascular Inflammation

Long Non-Coding RNAs in Vascular Inflammation

Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases

Long noncoding RNAs in lipid metabolism

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