期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 126, 期 -, 页码 60-69出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2018.11.001
关键词
NKILA; Methylation; Feedback loop; Endothelium inflammation
资金
- National Science Foundation of China [81771226, 81600987]
- Henan Province Foundation [162300410214, 19IRTSTHN003]
- Xinxiang City Foundation [CXRC16003, ZD17008]
- Xinxiang Medical University Foundation [2016PN-KFKT-03, 20172DCG-03]
Endothelium inflammation, a key event in vascular pathological process, can lead to endothelial activation and subsequent vascular disorders. Long non-coding RNA NKILA plays an important regulatory role in pro-inflammatory response. However, the underlying molecular basis by which NKILA regulates endothelial inflammation is poorly understood. In this study, we identify NKILA as a critical repressor to protect the endothelium from inflammation. Mechanistically, we show that NKILA is able to positively mediate the expression of KLF4, an anti-inflammatory atheroprotective regulator in endothelial cells (ECs), by a NF-kappa B-mediated DNA methylation mechanism. Moreover, NF-kappa B is found to help recruit DNMT3A to the CpG island of KLF4 promoter, facilitating KLF4 promoter DNA methylation and transcriptional repression. More importantly, we find KLF4 can inversely attenuate NF-kappa B transcriptional activity via establishing a NF-kappa B/KLF4 positive feedback loop, which is under the control of NKILA. Hence, sustained endothelium inflammation will occur, once the NKILA becomes dysfunctional. These studies revealed that NKILA can function as a vital regulator to protect the endothelium from inflammatory lesions and related vascular diseases.
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