PMID- 36284300 OWN - NLM STAT- MEDLINE DCOM- 20221027 LR - 20221103 IS - 1528-3658 (Electronic) IS - 1076-1551 (Print) IS - 1076-1551 (Linking) VI - 28 IP - 1 DP - 2022 Oct 25 TI - LncRNA FENDRR with m6A RNA methylation regulates hypoxia-induced pulmonary artery endothelial cell pyroptosis by mediating DRP1 DNA methylation. PG - 126 LID - 10.1186/s10020-022-00551-z [doi] LID - 126 AB - BACKGROUND: Pyroptosis is a form of programmed cell death involved in the pathophysiological progression of hypoxic pulmonary hypertension (HPH). Emerging evidence suggests that N6-methyladenosine (m6A)-modified transcripts of long noncoding RNAs (lncRNAs) are important regulators that participate in many diseases. However, whether m6A modified transcripts of lncRNAs can regulate pyroptosis in HPH progression remains unexplored. METHODS: The expression levels of FENDRR in hypoxic pulmonary artery endothelial cells (HPAECs) were detected by using quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). Western blot, Lactate dehydrogenase (LDH) release assay, Annexin V-FITC/PI double staining, Hoechst 33342/PI fluorescence staining and Caspase-1 activity assay were used to detect the role of FENDRR in HPAEC pyroptosis. The relationship between FENDRR and dynamin-related protein 1 (DRP1) was explored using bioinformatics analysis, Chromatin Isolation by RNA Purification (CHIRP), Electrophoretic mobility shift assay (EMSA) and Methylation-Specific PCR (MSP) assays. RNA immunoprecipitation (RIP) and m6A dot blot were used to detect the m6A modification levels of FENDRR. A hypoxia-induced mouse model of pulmonary hypertension (PH) was used to test preventive effect of conserved fragment TFO2 of FENDRR. RESULTS: We found that FENDRR was significantly downregulated in the nucleus of hypoxic HPAECs. FENDRR overexpression inhibited hypoxia-induced HPAEC pyroptosis. Additionally, DRP1 is a downstream target gene of FENDRR, and FENDRR formed an RNA-DNA triplex with the promoter of DRP1, which led to an increase in DRP1 promoter methylation that decreased the transcriptional level of DRP1. Notably, we illustrated that the m6A reader YTHDC1 plays an important role in m6A-modified FENDRR degradation. Additionally, conserved fragment TFO2 of FENDEE overexpression prevented HPH in vivo. CONCLUSION: In summary, our results demonstrated that m6A-induced decay of FENDRR promotes HPAEC pyroptosis by regulating DRP1 promoter methylation and thereby provides a novel potential target for HPH therapy. CI - (c) 2022. The Author(s). FAU - Wang, Xiaoying AU - Wang X AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. AD - College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China. FAU - Li, Qian AU - Li Q AD - College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China. FAU - He, Siyu AU - He S AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. AD - College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China. FAU - Bai, June AU - Bai J AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. AD - College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China. FAU - Ma, Cui AU - Ma C AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. AD - College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. FAU - Zhang, Lixin AU - Zhang L AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. AD - College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. FAU - Guan, Xiaoyu AU - Guan X AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. AD - College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China. FAU - Yuan, Hao AU - Yuan H AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. AD - College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China. FAU - Li, Yiying AU - Li Y AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. AD - College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China. FAU - Zhu, Xiangrui AU - Zhu X AD - College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. FAU - Mei, Jian AU - Mei J AD - College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. FAU - Gao, Feng AU - Gao F AD - College of Dental Medicine-Illinois, Midwestern University, Downers Grove, IL, 60515, USA. FAU - Zhu, Daling AU - Zhu D AUID- ORCID: 0000-0002-1008-9155 AD - Central Laboratory of Harbin Medical University (Daqing), Daqing, 163319, People's Republic of China. zhudaling@hrbmu.edu.cn. AD - College of Pharmacy, Harbin Medical University, Harbin, 150081, People's Republic of China. zhudaling@hrbmu.edu.cn. AD - Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Harbin, 150081, People's Republic of China. zhudaling@hrbmu.edu.cn. AD - College of Pharmacy, Harbin Medical University (Daqing), Xinyang Road, Daqing, 163319, Heilongjiang, People's Republic of China. zhudaling@hrbmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221025 PL - England TA - Mol Med JT - Molecular medicine (Cambridge, Mass.) JID - 9501023 RN - 0 (RNA, Long Noncoding) RN - EC 3.6.5.5 (Dynamins) RN - 0 (Chromatin) RN - EC 1.1.- (Lactate Dehydrogenases) RN - EC 3.4.22.- (Caspases) SB - IM MH - Mice MH - Animals MH - *RNA, Long Noncoding/genetics/metabolism MH - DNA Methylation MH - Endothelial Cells/metabolism MH - Pyroptosis MH - Pulmonary Artery MH - *Hypertension, Pulmonary/genetics MH - In Situ Hybridization, Fluorescence MH - Hypoxia/genetics MH - Dynamins/genetics/metabolism MH - Chromatin MH - Lactate Dehydrogenases/genetics/metabolism MH - Caspases PMC - PMC9594874 OTO - NOTNLM OT - Dynamin-related protein 1 OT - Pulmonary artery endothelial cells OT - Pyroptosis OT - lncRNA FENDRR OT - m6A RNA methylation COIS- The authors declare that they have no conflict of interest. EDAT- 2022/10/27 06:00 MHDA- 2022/10/28 06:00 PMCR- 2022/10/25 CRDT- 2022/10/26 00:28 PHST- 2022/02/11 00:00 [received] PHST- 2022/10/03 00:00 [accepted] PHST- 2022/10/26 00:28 [entrez] PHST- 2022/10/27 06:00 [pubmed] PHST- 2022/10/28 06:00 [medline] PHST- 2022/10/25 00:00 [pmc-release] AID - 10.1186/s10020-022-00551-z [pii] AID - 551 [pii] AID - 10.1186/s10020-022-00551-z [doi] PST - epublish SO - Mol Med. 2022 Oct 25;28(1):126. doi: 10.1186/s10020-022-00551-z.