Xinxing Zhu1, Yanli Liu2, Jinjin Yu3, Jiang Du1, Rui Guo1, Yanyan Feng4, Genshen Zhong5, Yizhou Jiang6, Juntang Lin7. 1. Henan Joint International Research Laboratory of Stem Cell Medicine, College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, 453003, Henan, China; Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China. 2. Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China. 3. School of Psychology, Xinxiang Medical University, Xinxiang, 453003, Henan, China. 4. Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University (Psychiatric Hospital of Henan Province, China), Jianshe Road 388, Xinxiang, 453002, Henan, China. 5. Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China. 6. Institute for Advanced Study, Shenzhen University, Shenzhen, 518000, Guangdong, China. Electronic address: 709723018@qq.com. 7. Henan Joint International Research Laboratory of Stem Cell Medicine, College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, 453003, Henan, China; Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China. Electronic address: 171062@xxmu.edu.cn.
Abstract
BACKGROUND AND AIMS: Endothelium inflammation, which can lead to endothelial activation and dysfunction, is widely accepted as the major event in multiple vascular disorders. The lncRNA HOXA-AS2 was previously reported to be involved in multiple inflammation-linked cancers. However, the role of HOXA-AS2 in endothelium inflammation is poorly understood. This study aims to determine the regulatory role of HOXA-AS2 in endothelium inflammation and related vascular diseases. METHODS: High throughput mRNA sequencing was performed to establish expression profiles after HOXA-AS2 depletion. We extracted total RNAs of human peripheral blood mononuclear cells from normal control group and experimental group with carotid artery atherosclerosis, and performed qRT-PCR to assay the correlation between HOXA-AS2 expression and inflammatory vascular diseases. RESULTS: Inhibition of HOXA-AS2 can induce the activation of NF-κB signaling and subsequent inflammatory response. More importantly, HOXA-AS2 is inversely found to be inversely regulated by NF-κB in a negative feedback manner by helping recruit BRD4/P-TEFb complex to HOXA-AS2 promoter region, therefore facilitating release of the promoter-proximal paused RNA polymerase II and activating transcription elongation. CONCLUSIONS: We identify HOXA-AS2 as a critical repressor of endothelium inflammation. Moreover, this study offers us a new way to balance the NF-κB signaling-driven excessive endothelium inflammation by establishing a NF-κB/HOXA-AS2 negative feedback loop. Based on these findings, we conclude that HOXA-AS2 may serve as a crucial therapeutic target for various vascular disorders which are significantly associated with endothelium inflammation.
BACKGROUND AND AIMS: Endothelium inflammation, which can lead to endothelial activation and dysfunction, is widely accepted as the major event in multiple vascular disorders. The lncRNA HOXA-AS2 was previously reported to be involved in multiple inflammation-linked cancers. However, the role of HOXA-AS2 in endothelium inflammation is poorly understood. This study aims to determine the regulatory role of HOXA-AS2 in endothelium inflammation and related vascular diseases. METHODS: High throughput mRNA sequencing was performed to establish expression profiles after HOXA-AS2 depletion. We extracted total RNAs of human peripheral blood mononuclear cells from normal control group and experimental group with carotid artery atherosclerosis, and performed qRT-PCR to assay the correlation between HOXA-AS2 expression and inflammatory vascular diseases. RESULTS: Inhibition of HOXA-AS2 can induce the activation of NF-κB signaling and subsequent inflammatory response. More importantly, HOXA-AS2 is inversely found to be inversely regulated by NF-κB in a negative feedback manner by helping recruit BRD4/P-TEFb complex to HOXA-AS2 promoter region, therefore facilitating release of the promoter-proximal paused RNA polymerase II and activating transcription elongation. CONCLUSIONS: We identify HOXA-AS2 as a critical repressor of endothelium inflammation. Moreover, this study offers us a new way to balance the NF-κB signaling-driven excessive endothelium inflammation by establishing a NF-κB/HOXA-AS2 negative feedback loop. Based on these findings, we conclude that HOXA-AS2 may serve as a crucial therapeutic target for various vascular disorders which are significantly associated with endothelium inflammation.