PMID- 34140262 OWN - NLM STAT- MEDLINE DCOM- 20210727 LR - 20220128 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 45 DP - 2021 Sep TI - Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells. PG - 102018 LID - S2213-2317(21)00176-2 [pii] LID - 10.1016/j.redox.2021.102018 [doi] LID - 102018 AB - Hyperhomocysteinemia (HHcy) is an established and potent independent risk factor for degenerative diseases, including cardiovascular disease (CVD), Alzheimer disease, type II diabetes mellitus, and chronic kidney disease. HHcy has been shown to inhibit proliferation and promote inflammatory responses in endothelial cells (EC), and impair endothelial function, a hallmark for vascular injury. However, metabolic processes and molecular mechanisms mediating HHcy-induced endothelial injury remains to be elucidated. This study examined the effects of HHcy on the expression of microRNA (miRNA) and mRNA in human aortic EC treated with a pathophysiologically relevant concentration of homocysteine (Hcy 500 muM). We performed a set of extensive bioinformatics analyses to identify HHcy-altered metabolic and molecular processes. The global functional implications and molecular network were determined by Gene Set Enrichment Analysis (GSEA) followed by Cytoscape analysis. We identified 244 significantly differentially expressed (SDE) mRNA, their relevant functional pathways, and 45 SDE miRNA. HHcy-altered SDE inversely correlated miRNA-mRNA pairs (45 induced/14 reduced mRNA) were discovered and applied to network construction using an experimentally verified database. We established a hypothetical model to describe the biochemical and molecular network with these specified miRNA/mRNA axes, finding: 1) HHcy causes metabolic reprogramming by increasing glucose uptake and oxidation, by glycogen debranching and NAD(+)/CoA synthesis, and by stimulating mitochondrial reactive oxygen species production via NNT/IDH2 suppression-induced NAD(+)/NADP-NADPH/NADP(+) metabolism disruption; 2) HHcy activates inflammatory responses by activating inflammasome-pyroptosis mainly through downward arrowmiR193b--> upward arrowCASP-9 signaling and by inducing IL-1beta and adhesion molecules through the downward arrowmiR29c--> upward arrowNEDD9 and the downward arrowmiR1256--> upward arrowICAM-1 axes, as well as GPCR and interferon alpha/beta signaling; 3) HHcy promotes cell degradation by the activation of lysosome autophagy and ubiquitin proteasome systems; 4) HHcy causes cell cycle arrest at G1/S and S/G2 transitions, suppresses spindle checkpoint complex and cytokinetic abscission, and suppresses proliferation through downward arrowmiRNA335/ upward arrowVASH1 and other axes. These findings are in accordance with our previous studies and add a wealth of heretofore-unexplored molecular and metabolic mechanisms underlying HHcy-induced endothelial injury. This is the first study to consider the effects of HHcy on both global mRNA and miRNA expression changes for mechanism identification. Molecular axes and biochemical processes identified in this study are useful not only for the understanding of mechanisms underlying HHcy-induced endothelial injury, but also for discovering therapeutic targets for CVD in general. CI - Copyright (c) 2021 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Jan, Michael AU - Jan M AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States; Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, United States. FAU - Cueto, Ramon AU - Cueto R AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Jiang, Xiaohua AU - Jiang X AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Lu, Liu AU - Lu L AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Sardy, Jason AU - Sardy J AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Xiong, Xinyu AU - Xiong X AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Yu, Justine E AU - Yu JE AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Pham, Hung AU - Pham H AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Khan, Mohsin AU - Khan M AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Qin, Xuebing AU - Qin X AD - Tulane National Primate Research Center, School of Medicine, Tulane University, Covington, LA, United States. FAU - Ji, Yong AU - Ji Y AD - Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. FAU - Yang, Xiao-Feng AU - Yang XF AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, United States. FAU - Wang, Hong AU - Wang H AD - Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, United States. Electronic address: hongw@temple.edu. LA - eng GR - P51 OD011104/OD/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20210524 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 0LVT1QZ0BA (Homocysteine) SB - IM MH - *Diabetes Mellitus, Type 2 MH - Endothelial Cells MH - Homocysteine MH - Humans MH - *Hyperhomocysteinemia/genetics MH - Oxidation-Reduction MH - Signal Transduction PMC - PMC8282538 OTO - NOTNLM OT - Degradation OT - Endothelial injury OT - Global mRNA/miRNA expression OT - Homocysteine OT - Inflammation OT - Metabolic reprogramming OT - Proliferation OT - Redox signaling COIS- The authors declare that they have no conflict of interest with respect to this manuscript. EDAT- 2021/06/19 06:00 MHDA- 2021/07/28 06:00 PMCR- 2021/05/24 CRDT- 2021/06/18 05:46 PHST- 2021/04/07 00:00 [received] PHST- 2021/05/13 00:00 [revised] PHST- 2021/05/19 00:00 [accepted] PHST- 2021/06/19 06:00 [pubmed] PHST- 2021/07/28 06:00 [medline] PHST- 2021/06/18 05:46 [entrez] PHST- 2021/05/24 00:00 [pmc-release] AID - S2213-2317(21)00176-2 [pii] AID - 102018 [pii] AID - 10.1016/j.redox.2021.102018 [doi] PST - ppublish SO - Redox Biol. 2021 Sep;45:102018. doi: 10.1016/j.redox.2021.102018. Epub 2021 May 24.