PMID- 33574979 OWN - NLM STAT- MEDLINE DCOM- 20210518 LR - 20231115 IS - 1942-0994 (Electronic) IS - 1942-0900 (Print) IS - 1942-0994 (Linking) VI - 2021 DP - 2021 TI - GSTM1 Modulates Expression of Endothelial Adhesion Molecules in Uremic Milieu. PG - 6678924 LID - 10.1155/2021/6678924 [doi] LID - 6678924 AB - Deletion polymorphism of glutathione S-transferase M1 (GSTM1), a phase II detoxification and antioxidant enzyme, increases susceptibility to end-stage renal disease (ESRD) as well as the development of cardiovascular diseases (CVD) among ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory cytokines including retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (RANTES), C-reactive protein (CRP), angiogenin, dickkopf-1 (Dkk-1), and platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) were increased in ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altered expression of a series of cytokines involved in arteriosclerosis and atherosclerosis. The association of GSTM1 downregulation with the altered expression of adhesion molecules might be at least partly responsible for the increased susceptibility of ESRD patients to CVD. CI - Copyright (c) 2021 Djurdja Jerotic et al. FAU - Jerotic, Djurdja AU - Jerotic D AUID- ORCID: 0000-0002-1664-6557 AD - Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. FAU - Suvakov, Sonja AU - Suvakov S AD - Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. FAU - Matic, Marija AU - Matic M AD - Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. FAU - Alqudah, Abdelrahim AU - Alqudah A AD - Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, P.O. Box 330127 Zarqa 13133, Jordan. AD - The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. FAU - Grieve, David J AU - Grieve DJ AD - The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. FAU - Pljesa-Ercegovac, Marija AU - Pljesa-Ercegovac M AD - Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. FAU - Savic-Radojevic, Ana AU - Savic-Radojevic A AD - Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. FAU - Damjanovic, Tatjana AU - Damjanovic T AD - Clinical Department for Renal Diseases, Zvezdara University Medical Center, 11000 Belgrade, Serbia. FAU - Dimkovic, Nada AU - Dimkovic N AD - Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Clinical Department for Renal Diseases, Zvezdara University Medical Center, 11000 Belgrade, Serbia. FAU - McClements, Lana AU - McClements L AUID- ORCID: 0000-0002-4911-1014 AD - The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. AD - School of Life Sciences, Faculty of Science, University of Technology Sydney, 2007, NSW, Australia. FAU - Simic, Tatjana AU - Simic T AUID- ORCID: 0000-0001-8683-5129 AD - Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. AD - Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia. LA - eng GR - FS/14/35/30813/BHF_/British Heart Foundation/United Kingdom GR - PG/14/78/31099/BHF_/British Heart Foundation/United Kingdom GR - PG/19/61/34586/BHF_/British Heart Foundation/United Kingdom PT - Journal Article DEP - 20210125 PL - United States TA - Oxid Med Cell Longev JT - Oxidative medicine and cellular longevity JID - 101479826 RN - 0 (Biomarkers) RN - 0 (Cytokines) RN - 0 (Proteome) RN - 0 (Reactive Oxygen Species) RN - 0 (Vascular Cell Adhesion Molecule-1) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) RN - 4Y8F71G49Q (Malondialdehyde) RN - EC 1.11.1.9 (Glutathione Peroxidase) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.5.1.18 (Glutathione Transferase) RN - EC 2.5.1.18 (glutathione S-transferase M1) SB - IM MH - Biomarkers/metabolism MH - Cytokines/metabolism MH - Gene Deletion MH - Glutathione Peroxidase/metabolism MH - Glutathione Transferase/*metabolism MH - Human Umbilical Vein Endothelial Cells/*metabolism MH - Humans MH - Intercellular Adhesion Molecule-1/*metabolism MH - Kidney Failure, Chronic/blood/metabolism MH - Malondialdehyde/metabolism MH - Oxidative Stress MH - Proteome/metabolism MH - Reactive Oxygen Species/metabolism MH - Superoxide Dismutase/metabolism MH - Uremia/blood/*metabolism MH - Vascular Cell Adhesion Molecule-1/*metabolism PMC - PMC7860968 COIS- The authors declare that they have no conflict of interest. EDAT- 2021/02/13 06:00 MHDA- 2021/05/19 06:00 PMCR- 2021/01/25 CRDT- 2021/02/12 06:08 PHST- 2020/11/20 00:00 [received] PHST- 2020/12/22 00:00 [revised] PHST- 2020/12/26 00:00 [accepted] PHST- 2021/02/12 06:08 [entrez] PHST- 2021/02/13 06:00 [pubmed] PHST- 2021/05/19 06:00 [medline] PHST- 2021/01/25 00:00 [pmc-release] AID - 10.1155/2021/6678924 [doi] PST - epublish SO - Oxid Med Cell Longev. 2021 Jan 25;2021:6678924. doi: 10.1155/2021/6678924. eCollection 2021.