The Long Noncoding RNA RP11-728F11.4 Promotes Atherosclerosis

Author:

Dong Xian-Hui1ORCID,Lu Zhi-Feng2,Kang Chun-Min2,Li Xue-Heng2,Haworth Kim E.3,Ma Xin4,Lu Jing-Bo56,Liu Xue-Hui2,Fang Fu-Chun7ORCID,Wang Claire S.8ORCID,Ye John H.9ORCID,Zheng Lei2,Wang Qian2,Ye Shu310ORCID,Hu Yan-Wei12

Affiliation:

1. Department of Clinical Laboratory, Guangzhou Women and Children Medical Center, Guangzhou Medical University, China (X.-H.D., Y.-W.H.).

2. Laboratory Medicine Center (Z.-F.L., C.-M.K., X.-H. Li, X.-H. Liu, L.Z., Q.W., Y.-W.H.), Nanfang Hospital, Southern Medical University, Guangzhou, China.

3. Department of Cardiovascular Sciences and NIHR (National Institute for Health Research) Leicester Biomedical Research Centre, University of Leicester, United Kingdom (K.E.H., S.Y.).

4. Department of Anesthesiology (X.M.), Nanfang Hospital, Southern Medical University, Guangzhou, China.

5. Department of Vascular Surgery (J.-B.L.), Nanfang Hospital, Southern Medical University, Guangzhou, China.

6. Department of Vascular Surgery, Shenzhen Sun Yat-Sen Cardiovascular Hospital, China (J.-B.L.).

7. Department of Stomatology (F.-C.F.), Nanfang Hospital, Southern Medical University, Guangzhou, China.

8. Gonville and Caius College, University of Cambridge, United Kindgom (C.S.W.).

9. University Hospitals of Leicester NHS Trust, United Kingdom (J.H.Y.).

10. Shantou University Medical College, China (S.Y.).

Abstract

Objective: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na + /K + -ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na + /K + -ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. Conclusions: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target. Graphic Abstract: A graphic abstract is available for this article.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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