Silencing of Long Non-Coding RNA H19 Protects Against Atherosclerosis by Upregulating CTCF-Mediated PKD1 in ApoE Knockout Mice

Abstract

Background: Atherosclerosis (AS) is highlighted as the leading cause of death worldwide. Although the important roles of long non-coding RNAs (lncRNAs) have been emphasized in AS, the underlying mechanism still remain less understood. Therefore, this study aimed to explore the potential regulatory role of H19 in the vulnerable plaque formation and angiogenesis of AS. Methods: In order to elucidate the function of H19 in AS and the relationships among H19, transcriptional factor CCCTC-binding factor (CTCF) and polycystic kidney disease 1 (PKD1), AS mouse model was established using ApoE knockout mouse. The potential relationships among them and the effects of H19 and PKD1 on vulnerable plaque formation and angiogenesis in AS were investigated using gain- and loss-of-function approaches. H19 was expressed at a high level in aortic tissues of AS mice. Silencing. Results: H19 was shown to significantly inhibit the atherosclerotic vulnerable plaque formation and intraplague angiogenesis and downregulate the expression of angiogenesis-related factors matrix metalloproteinase 2 (MMP-2), vascular endothelial growth-factor (VEGF) and p53 and upregulate that of tissue inhibitor of metalloproteinases-1 (TIMP-1). However, opposite results were found in aortic tissues of AS mice overexpressing H19 or CTCF. H19 was capable of recruiting CTCF to suppress the transcriptional level of PKD1, thus promoting atherosclerotic vulnerable plaque formation and intraplaque angiogenesis in AS mice. Conclusions: Taken together, the key findings of the present study provided evidence that functional suppression of H19 prevented atherosclerotic vulnerable plaque formation and intraplaque angiogenesis by promoting the transcriptional level of PKD1 through attenuated ability to recruit CTCF. Funding: This study was supported by the National Natural Science Foundation of China [NO. 81660080] and the National Key-Specialty Construction Project of China [NO. (2013)544] and the Clinical Research Center Project of the Department of Science and Technology of Guizhou Province [NO. (2017)5405]. Declaration of Interest: The authors declare that they have no conflicts of interest. Ethical Approval: The experimental procedures were approved by the Institutional Animal Care and Use Committee of Guizhou Provincial People’s Hospital.