Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells
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 response...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721001762 |
| _version_ | 1819119594849173504 |
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| author | Michael Jan Ramon Cueto Xiaohua Jiang Liu Lu Jason Sardy Xinyu Xiong Justine E. Yu Hung Pham Mohsin Khan Xuebing Qin Yong Ji Xiao-Feng Yang Hong Wang |
| author_facet | Michael Jan Ramon Cueto Xiaohua Jiang Liu Lu Jason Sardy Xinyu Xiong Justine E. Yu Hung Pham Mohsin Khan Xuebing Qin Yong Ji Xiao-Feng Yang Hong Wang |
| author_sort | Michael Jan |
| collection | DOAJ |
| description | 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 μM). 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 ↓miR193b→↑CASP-9 signaling and by inducing IL-1β and adhesion molecules through the ↓miR29c→↑NEDD9 and the ↓miR1256→↑ICAM-1 axes, as well as GPCR and interferon α/β 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 ↓miRNA335/↑VASH1 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. |
| first_indexed | 2024-12-22T06:07:16Z |
| format | Article |
| id | doaj.art-3e4372b71831405a9794244a9c28f883 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-22T06:07:16Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-3e4372b71831405a9794244a9c28f8832022-12-21T18:36:21ZengElsevierRedox Biology2213-23172021-09-0145102018Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cellsMichael Jan0Ramon Cueto1Xiaohua Jiang2Liu Lu3Jason Sardy4Xinyu Xiong5Justine E. Yu6Hung Pham7Mohsin Khan8Xuebing Qin9Yong Ji10Xiao-Feng Yang11Hong Wang12Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States; Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, United StatesCenter for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United StatesCenter for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United StatesCenter for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United StatesCenter for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United StatesCenter for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United StatesCenter for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United StatesCenter for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United StatesCenter for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United StatesTulane National Primate Research Center, School of Medicine, Tulane University, Covington, LA, United StatesKey Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, ChinaCenter 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 StatesCenter 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; Corresponding author. Center for Metabolic Disease Research, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, United States.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 μM). 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 ↓miR193b→↑CASP-9 signaling and by inducing IL-1β and adhesion molecules through the ↓miR29c→↑NEDD9 and the ↓miR1256→↑ICAM-1 axes, as well as GPCR and interferon α/β 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 ↓miRNA335/↑VASH1 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.http://www.sciencedirect.com/science/article/pii/S2213231721001762HomocysteineGlobal mRNA/miRNA expressionEndothelial injuryMetabolic reprogrammingRedox signalingInflammation |
| spellingShingle | Michael Jan Ramon Cueto Xiaohua Jiang Liu Lu Jason Sardy Xinyu Xiong Justine E. Yu Hung Pham Mohsin Khan Xuebing Qin Yong Ji Xiao-Feng Yang Hong Wang Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells Redox Biology Homocysteine Global mRNA/miRNA expression Endothelial injury Metabolic reprogramming Redox signaling Inflammation |
| title | Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells |
| title_full | Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells |
| title_fullStr | Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells |
| title_full_unstemmed | Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells |
| title_short | Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells |
| title_sort | molecular processes mediating hyperhomocysteinemia induced metabolic reprogramming redox regulation and growth inhibition in endothelial cells |
| topic | Homocysteine Global mRNA/miRNA expression Endothelial injury Metabolic reprogramming Redox signaling Inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231721001762 |
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