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Super-enhancers (SEs) typically govern the expression of critical genes in the maintenance of cell identity. Recent advances suggest mitochondrial dysfunction contributes to pulmonary artery smooth muscle cell (PASMC) proliferation and inflammation in pulmonary hypertension (PH). However, the landscape of SEs in hypoxic PASMCs as well as hypoxia-induced target genes associated with SEs controlling the mitochondrial dysfunction remain to be fully characterized. In this study, we depicted the landscape of SE in hypoxic PASMCs by ChIP-seq, Hi-ChIP, and ChIP-qPCR assays and reveal a regulatory SE driven LncRNA, LINC01013. The effect of LINC01013 on proliferation and inflammation of PASMCs was evaluated through EdU incorporation, Western blotting and immunofluorescence. The molecular mechanism of LINC01013 was investigated by the study of RNA pull down and mass spectrometry. We profiled chromosome interactions in epigenetic regulation and identified SE-associated LINC01013 as a key mitochondrial dysfunction mediator in hypoxic PASMCs. The transcription factor CCAAT enhancer binding protein beta (CEBPB) was found to enrichment in LINC01013 SE and promoter, promoting LINC01013 transcription and overexpression in PASMCs under hypoxic conditions. Inhibition of LINC01013 reversed hypoxia-induced glycolysis and oxidative stress injury of PASMCs. Further investigation unveiled that LINC01013, which is partially located in mitochondria and interacted with heat shock protein family A member 9 (HSPA9) to mediate oligomerization of voltage dependent anion channel 1 (VDAC1), thereby leading to increased mitochondrial permeability and dysfunction. These findings demonstrate that SE-associated LINC01013 regulates the proliferation and inflammation of hypoxic PASMCs by orchestrating mitochondrial function, might be a potential therapeutic target for PH.

The 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. The 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. In 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-1β, IL-6, and TNF-α by influencing the glycolytic pathway in PASMCs under hypoxic conditions, ultimately affecting the inflammatory phenotype transition of PASMCs. Our 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. The 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-1β, IL-6, and TNF-α promoters, leading to the inflammatory phenotype transition of PASMCs. Overexpression of lncRNA UNC5B-AS1 conserved fragment reversed SuHx-induced PH in mice. biorxiv;2024.05.07.593065v1/UFIG1F1ufig1