LncRNA PSMB8-AS1 Instigates Vascular Inflammation to Aggravate Atherosclerosis

Shu Li; Run-Chao He; Shao-Guo Wu; Yu Song; Ke-Lan Zhang; Mao-Lin Tang; Yan-Rou Bei; Ting Zhang; Jin-Bo Lu; Xin Ma; Min Jiang; Liang-Jun Qin; Yudan Xu; Xian-Hui Dong; Jia Wu; Xiaoyan Dai; Yan-Wei Hu

doi:10.1161/CIRCRESAHA.122.322360

LncRNA PSMB8-AS1 Instigates Vascular Inflammation to Aggravate Atherosclerosis

Circ Res. 2024 Jan 5;134(1):60-80. doi: 10.1161/CIRCRESAHA.122.322360. Epub 2023 Dec 12.

Authors

Shu Li^#¹, Run-Chao He^#¹, Shao-Guo Wu^#², Yu Song^#¹, Ke-Lan Zhang¹, Mao-Lin Tang¹, Yan-Rou Bei³, Ting Zhang¹, Jin-Bo Lu⁴, Xin Ma⁵, Min Jiang¹, Liang-Jun Qin⁶, Yudan Xu⁷, Xian-Hui Dong¹, Jia Wu¹, Xiaoyan Dai^{8

9}, Yan-Wei Hu^{1

10}

Affiliations

¹ Department of Clinical Laboratory, Guangzhou Women & Children Medical Center, Guangzhou Medical University, Guangdong, China (S.L., R.-C.H., Y.S., K.-L.Z., M.-L.T., T.Z., M.J., X.-H.D., J.W., Y.-W.H.).
² Department of Clinical Laboratory, Guangzhou Twelfth People's Hospital, Guangdong, China (S.-G.W.).
³ Laboratory Medicine Center (Y.-R.B.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
⁴ Department of Peripheral Vascular Surgery, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen (J.-B.L.).
⁵ Department of Anesthesiology (X.M.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
⁶ Department of Pathology, Guangzhou Women & Children Medical Center, Guangzhou Medical University, Guangdong, China (L.J.Q.).
⁷ Laboratory Medicine Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (Y.X.).
⁸ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangdong, China (X.D.).
⁹ Clinical Research Institute, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China (X.D.).
¹⁰ Department of Laboratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Y.-W.H.).

^# Contributed equally.

PMID: 38084631
DOI: 10.1161/CIRCRESAHA.122.322360

Abstract

Background: Increasing evidence suggests that long noncoding RNAs play significant roles in vascular biology and disease development. One such long noncoding RNA, PSMB8-AS1, has been implicated in the development of tumors. Nevertheless, the precise role of PSMB8-AS1 in cardiovascular diseases, particularly atherosclerosis, has not been thoroughly elucidated. Thus, the primary aim of this investigation is to assess the influence of PSMB8-AS1 on vascular inflammation and the initiation of atherosclerosis.

Methods: We generated PSMB8-AS1 knockin and Apoe (Apolipoprotein E) knockout mice (Apoe^-/-PSMB8-AS1^KI) and global Apoe and proteasome subunit-β type-9 (Psmb9) double knockout mice (Apoe^-/-Psmb9^-/-). To explore the roles of PSMB8-AS1 and Psmb9 in atherosclerosis, we fed the mice with a Western diet for 12 weeks.

Results: Long noncoding RNA PSMB8-AS1 is significantly elevated in human atherosclerotic plaques. Strikingly, Apoe^-/-PSMB8-AS1^KI mice exhibited increased atherosclerosis development, plaque vulnerability, and vascular inflammation compared with Apoe^-/- mice. Moreover, the levels of VCAM1 (vascular adhesion molecule 1) and ICAM1 (intracellular adhesion molecule 1) were significantly upregulated in atherosclerotic lesions and serum of Apoe^-/-PSMB8-AS1^KI mice. Consistently, in vitro gain- and loss-of-function studies demonstrated that PSMB8-AS1 induced monocyte/macrophage adhesion to endothelial cells and increased VCAM1 and ICAM1 levels in a PSMB9-dependent manner. Mechanistic studies revealed that PSMB8-AS1 induced PSMB9 transcription by recruiting the transcription factor NONO (non-POU domain-containing octamer-binding protein) and binding to the PSMB9 promoter. PSMB9 (proteasome subunit-β type-9) elevated VCAM1 and ICAM1 expression via the upregulation of ZEB1 (zinc finger E-box-binding homeobox 1). Psmb9 deficiency decreased atherosclerotic lesion size, plaque vulnerability, and vascular inflammation in Apoe^-/- mice in vivo. Importantly, endothelial overexpression of PSMB8-AS1-increased atherosclerosis and vascular inflammation were attenuated by Psmb9 knockout.

Conclusions: PSMB8-AS1 promotes vascular inflammation and atherosclerosis via the NONO/PSMB9/ZEB1 axis. Our findings support the development of new long noncoding RNA-based strategies to counteract atherosclerotic cardiovascular disease.

Keywords: adhesion molecule; atherosclerosis; cardiovascular diseases; knockout; vascular inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoproteins E / genetics
Atherosclerosis* / metabolism
Endothelial Cells / metabolism
Humans
Inflammation / genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Plaque, Atherosclerotic* / pathology
Proteasome Endopeptidase Complex / genetics
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism

Substances

Apolipoproteins E
Proteasome Endopeptidase Complex
RNA, Long Noncoding
LMP7 protein