Silencing of long non-coding RNA H19 downregulates CTCF to protect against atherosclerosis by upregulating PKD1 expression in ApoE knockout mice.

Yongyao Yang,Qiang Wu,Chunyan Kuang,Long Yang,Hongming Zhang,Feng Tang,Jiusheng Deng,Fang Wei

doi:10.18632/aging.102388

Silencing of long non-coding RNA H19 downregulates CTCF to protect against atherosclerosis by upregulating PKD1 expression in ApoE knockout mice.

Yongyao Yang, Qiang Wu + Show 6 more

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https://doi.org/10.18632/aging.102388

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Abstract

This study aimed to explore the interactions among long non-coding RNA H19, transcriptional factor CCCTC-binding factor (CTCF) and polycystic kidney disease 1 (PKD1), and to investigate its potentially regulatory effect on vulnerable plaque formation and angiogenesis of atherosclerosis. We established an atherosclerosis mouse model in ApoE knockout mice, followed by gain- and loss-of-function approaches. H19 was upregulated in aortic tissues of atherosclerosis mice, but silencing of H19 significantly inhibited atherosclerotic vulnerable plaque formation and intraplaque angiogenesis, accompanied by a downregulated expression of MMP-2, VEGF, and p53 and an upregulated expression of TIMP-1. Moreover, opposite results were found in the aortic tissues of atherosclerosis mice treated with H19 or CTCF overexpression. H19 was capable of recruiting CTCF to suppress PKD1, thus promoting atherosclerotic vulnerable plaque formation and intraplaque angiogenesis in atherosclerosis mice. The present study provides evidence that H19 recruits CTCF to downregulate the expression of PKD1, thereby promoting vulnerable plaque formation and intraplaque angiogenesis in mice with atherosclerosis.

Highlights

Atherosclerosis (AS), as the leading cause of stroke and myocardial infarction is prone to result in disability and mortality accounting for more than 50% of casualty cases worldwide [1]
Critical evidence based on examination of human atherosclerosis specimens suggested that H19 was predominantly expressed in the endothelial cell, where its expression was significantly down-regulated in pathological www.aging-us.com samples compared with healthy carotid artery biopsies [19]
Despite efforts made in exploring pathogenesis and advancing therapeutic methods, AS still poses a great threat to human health around the world [20]

Summary

Introduction

Atherosclerosis (AS), as the leading cause of stroke and myocardial infarction is prone to result in disability and mortality accounting for more than 50% of casualty cases worldwide [1]. The involvement of chronic inflammation is acknowledged to be an intrinsic factor in the initiation and progression of AS, leading to plaque rupture, thrombosis and vascular occlusion [2]. The rupture of unstable atherosclerotic plaques is a precursor of acute coronary syndromes, known as a major complication of AS. Pathological angiogenesis of the vessel is a frequently described characteristic aspect of the development and progression of atherosclerotic plaques in AS [4]. Angiogenesis plays an important role in both the initiation and late plaque rupture that lead to stroke and myocardial infarction [5]. Due to limitations of the available therapeutic pathways that might effectively reduce atherosclerotic vulnerable plaque formation and intraplaque angiogenesis, there is an urgent need for developing novel approaches to treat AS. Previous reports have flagged the involvement of long non-coding RNA (lncRNA) in the regulation of AS [6], which provides new insight for a preclinical investigation based on lncRNA-targeted therapy

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