Abstract
Long noncoding RNAs (lncRNAs) play important roles in regulating diverse cellular processes in the vessel wall, including atherosclerosis. RNA-Seq profiling of intimal lesions revealed a lncRNA, VINAS (Vascular INflammation and Atherosclerosis lncRNA Sequence), that is enriched in the aortic intima and regulates vascular inflammation. Aortic intimal expression of VINAS fell with atherosclerotic progression and rose with regression. VINAS knockdown reduced atherosclerotic lesion formation by 55% in LDL receptor–deficient (LDLR–/–) mice, independent of effects on circulating lipids, by decreasing inflammation in the vessel wall. Loss- and gain-of-function studies in vitro demonstrated that VINAS serves as a critical regulator of inflammation by modulating NF-κB and MAPK signaling pathways. VINAS knockdown decreased the expression of key inflammatory markers, such as MCP-1, TNF-α, IL-1β, and COX-2, in endothelial cells (ECs), vascular smooth muscle cells, and bone marrow–derived macrophages. Moreover, VINAS silencing decreased expression of leukocyte adhesion molecules VCAM-1, E-selectin, and ICAM-1 and reduced monocyte adhesion to ECs. DEP domain containing 4 (DEPDC4), an evolutionary conserved human ortholog of VINAS with approximately 74% homology, showed similar regulation in human and pig atherosclerotic specimens. DEPDC4 knockdown replicated antiinflammatory effects of VINAS in human ECs. These findings reveal a potentially novel lncRNA that regulates vascular inflammation, with broad implications for vascular diseases.
Highlights
Accumulating studies highlight that inflammatory processes and traditional cardiac risk factors may cooperatively contribute to vascular disease leading to the development of cardiovascular events [1, 2]
Eight Long noncoding RNAs (lncRNAs) rose with atherosclerosis progression and fell during regression, whereas only 3 lncRNAs decreased with atherosclerosis progression (Figure 1C)
This study provides evidence for the first time to our knowledge that the mouse-specific lncRNA VINAS and its human ortholog, DEP domain containing 4 (DEPDC4), play important roles in vascular inflammation and atherogenesis
Summary
Accumulating studies highlight that inflammatory processes and traditional cardiac risk factors may cooperatively contribute to vascular disease leading to the development of cardiovascular events [1, 2]. Impaired endothelial barrier function accompanies vascular inflammation and atherosclerosis [1, 8]. Similar to ECs, smooth muscle cells (SMCs) can express a variety of adhesion molecules in response to cytokine stimulation to which monocytes and lymphocytes can adhere and migrate into the vessel wall [5, 9, 10]. Major mechanistic gaps remain in our understanding of regulatory pathways involved in homeostasis of the vessel wall in response to pathophysiological stimuli, contributing to the dearth of targeted therapeutics in a range of vascular disease states
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