LncRNA HSPA7 in human atherosclerotic plaques sponges miR-223 and promotes the proinflammatory vascular smooth muscle cell transition

Abstract

Although there are many genetic loci in noncoding regions associated with vascular disease, studies on long noncoding RNAs (lncRNAs) discovered from human plaques that affect atherosclerosis have been highly limited. We aimed to identify and functionally validate a lncRNA using human atherosclerotic plaques. Human aortic samples were obtained from patients who underwent aortic surgery, and tissues were classified according to atherosclerotic plaques. RNA was extracted and analyzed for differentially expressed lncRNAs in plaques. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low-density lipoprotein (oxLDL) to evaluate the effect of the identified lncRNA on the inflammatory transition of the cells. Among 380 RNAs differentially expressed between the plaque and control tissues, lncRNA HSPA7 was selected and confirmed to show upregulated expression upon oxLDL treatment. HSPA7 knockdown inhibited the migration of HASMCs and the secretion and expression of IL-1β and IL-6; however, HSPA7 knockdown recovered the oxLDL-induced reduction in the expression of contractile markers. Although miR-223 inhibition promoted the activity of Nf-κB and the secretion of inflammatory proteins such as IL-1β and IL-6, HSPA7 knockdown diminished these effects. The effects of miR-223 inhibition and HSPA7 knockdown were also found in THP-1 cell-derived macrophages. The impact of HSPA7 on miR-223 was mediated in an AGO2-dependent manner. HSPA7 is differentially increased in human atheroma and promotes the inflammatory transition of vascular smooth muscle cells by sponging miR-223. For the first time, this study elucidated the molecular mechanism of action of HSPA7, a lncRNA of previously unknown function, in humans.

Atherosclerosis: Identifying noncoding RNA effect

A long non-coding RNA (lncRNA) called HSPA7 promotes the development of atherosclerosis, plaque in arteries. Many atherosclerosis-related genetic loci are in noncoding regions of genome, but there has been an incomplete understanding of them. Sang-Hak Lee at Yonsei University College of Medicine, Seoul, South Korea, and co-workers set out to identify a lncRNA involved in atherosclerosis and investigate its mode of action. Comparison of aortic tissues allowed them to identify lncRNAs more abundant in atherosclerotic tissue but less in healthy tissue. Of the 380 lncRNAs identified, only HSPA7 reliably increased when aortic cells were treated with a trigger of atherosclerosis. Inhibiting HSPA7 restored normal function in vascular cells, decreasing migration and inflammation. Further investigation showed that HSPA7 blocks the activity of miR-223, a microRNA that suppresses inflammation. These results identify a potential therapeutic target for atherosclerosis.