Super Enhancer-driven LncRNA UNC5B-AS1 Inhibits Inflammatory Phenotypic Transition in Smooth Muscle Cells via Lactylation Modification

Abstract

BackgroundThe phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) is a central pathological alteration in pulmonary artery remodeling that contributes to pulmonary hypertension (PH). The specific role of long noncoding RNAs (lncRNAs), especially super enhancer (SE)-driven lncRNAs, in the phenotypic transformation of PASMCs induced by hypoxia remains unclear. The objective of this study is to determine the mechanistic role of the super enhancer-driven LncRNA UNC5B-AS1 in phenotypic transformation of PASMCs and hypoxia-induced vascular remodeling. MethodsThe lncRNA UNC5B-AS1 regulated by super-enhancers was identified in hypoxic human PASMCs through RNA sequencing and H3K27ac ChIP sequencing. Overexpression of lncRNA UNC5B-AS1 in human PASMCs was performed to elucidate its role in the pathogenesis of PH. A conserved functional fragment of lncRNA UNC5B-AS1 was used for the treatment of mouse PH. ResultsIn PASMCs, we have identified a SE-driven lncRNA called UNC5B-AS1 that regulates phenotype transition. It is transcriptionally activated by the transcription factor FOXP3. We demonstrate that UNC5B-AS1, as a molecular scaffold in mitochondria, stabilizes the interaction between LRPPRC, which is rich in leucine, and oxidative respiratory chain complex IV. This complex regulates the lactylation modification level of upstream promoter regions of inflammatory genes IL-1{beta}, IL-6, and TNF- by influencing the glycolytic pathway in PASMCs under hypoxic conditions, ultimately affecting the inflammatory phenotype transition of PASMCs. ConclusionsOur findings identify the SE-driven lncRNA UNC5B-AS1 as a novel regulatory factor in hypoxia-induced phenotypic switch of PASMCs, and suggest that overexpression of UNC5B-AS1 may represent a promising therapeutic strategy for PH. HighlightsThe long non-coding RNA UNC5B-AS1, regulated by super-enhancers (SE), is downregulated in hypoxic PASMCs, and regulates PASMC phenotype transition through glycolysis. The super-enhancer region of lncRNA UNC5B-AS1 recruits the transcription factor FOXP3 to its promoter region, forming a chromatin loop to regulate its expression. The lncRNA UNC5B-AS1 acts as a molecular scaffold stabilizing the interaction between LRPPRC and mitochondrial complex IV. The lactate generated by glycolysis activation induces lactylation modification of histones at the IL-1{beta}, IL-6, and TNF- promoters, leading to the inflammatory phenotype transition of PASMCs. Overexpression of lncRNA UNC5B-AS1 conserved fragment reversed SuHx-induced PH in mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/593065v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@864576org.highwire.dtl.DTLVardef@13a5fe4org.highwire.dtl.DTLVardef@16d7884org.highwire.dtl.DTLVardef@35d50_HPS_FORMAT_FIGEXP M_FIG C_FIG