LncRNA <i>PSMB8-AS1</i> Instigates Vascular Inflammation to Aggravate Atherosclerosis.

Abstract

Increasing evidence suggests that long noncoding RNAs play significant roles in vascular biology and disease development. One such long noncoding RNA, <i>PSMB8-AS1</i>, has been implicated in the development of tumors. Nevertheless, the precise role of <i>PSMB8-AS1</i> in cardiovascular diseases, particularly atherosclerosis, has not been thoroughly elucidated. Thus, the primary aim of this investigation is to assess the influence of <i>PSMB8-AS1</i> on vascular inflammation and the initiation of atherosclerosis. We generated <i>PSMB8-AS1</i> knockin and <i>Apoe</i> (Apolipoprotein E) knockout mice (<i>Apoe^-/-PSMB8-AS1^KI</i>) and global <i>Apoe</i> and proteasome subunit-β type-9 (<i>Psmb9</i>) double knockout mice (<i>Apoe^-/-Psmb9^-/-</i>). To explore the roles of <i>PSMB8-AS1</i> and <i>Psmb9</i> in atherosclerosis, we fed the mice with a Western diet for 12 weeks. Long noncoding RNA <i>PSMB8-AS1</i> is significantly elevated in human atherosclerotic plaques. Strikingly, <i>Apoe^-/-PSMB8-AS1^KI</i> mice exhibited increased atherosclerosis development, plaque vulnerability, and vascular inflammation compared with <i>Apoe^-/-</i> 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 <i>Apoe^-/-PSMB8-AS1^KI</i> mice. Consistently, in vitro gain- and loss-of-function studies demonstrated that <i>PSMB8-AS1</i> induced monocyte/macrophage adhesion to endothelial cells and increased VCAM1 and ICAM1 levels in a PSMB9-dependent manner. Mechanistic studies revealed that <i>PSMB8-AS1</i> induced <i>PSMB9</i> transcription by recruiting the transcription factor NONO (non-POU domain-containing octamer-binding protein) and binding to the <i>PSMB9</i> promoter. PSMB9 (proteasome subunit-β type-9) elevated VCAM1 and ICAM1 expression via the upregulation of ZEB1 (zinc finger E-box-binding homeobox 1). <i>Psmb9</i> deficiency decreased atherosclerotic lesion size, plaque vulnerability, and vascular inflammation in <i>Apoe^-/-</i> mice in vivo. Importantly, endothelial overexpression of <i>PSMB8-AS1</i>-increased atherosclerosis and vascular inflammation were attenuated by <i>Psmb9</i> knockout. <i>PSMB8-AS1</i> promotes vascular inflammation and atherosclerosis via the NONO<i>/</i>PSMB9/ZEB1 axis. Our findings support the development of new long noncoding RNA-based strategies to counteract atherosclerotic cardiovascular disease.