title: Inhibition of homocysteine-induced endoplasmic reticulum stress and endothelial cell damage by l-serine and glycine.
abstract: Hyperhomocysteinemia is an independent risk factor for several cardiovascular diseases. The use of vitamins to modulate homocysteine metabolism substantially lowers the risk by reducing plasma homocysteine levels. In this study, we evaluated the effects of l-serine and related amino acids on homocysteine-induced endoplasmic reticulum (ER) stress and endothelial cell damage using EA.hy926 human endothelial cells. Homocysteine treatment decreased cell viability and increased apoptosis, which were reversed by cotreatment with l-serine. l-Serine inhibited homocysteine-induced ER stress as verified by decreased glucose-regulated protein 78kDa (GRP78) and C/EBP homologous protein (CHOP) expression as well as X-box binding protein 1 (xbp1) mRNA splicing. The effects of l-serine on homocysteine-induced ER stress are not attributed to intracellular homocysteine metabolism, but instead to decreased homocysteine uptake. Glycine exerted effects on homocysteine-induced ER stress, apoptosis, and cell viability that were comparable to those of l-serine. Although glycine did not affect homocysteine uptake or export, coincubation of homocysteine with glycine for 24h reduced the intracellular concentration of homocysteine. Taken together, l-serine and glycine cause homocysteine-induced endothelial cell damage by reducing the level of intracellular homocysteine. l-Serine acts by competitively inhibiting homocysteine uptake in the cells. However, the mechanism(s) by which glycine lowers homocysteine levels are unclear.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: masercat@naver.com.
authors.forename: Woo-Cheol
authors.initials: WC
authors.lastname: Sim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: hanih420@naver.com.
authors.forename: Inhoi
authors.initials: I
authors.lastname: Han
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: wonseokpharm@gmail.com.
authors.forename: Wonseok
authors.initials: W
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: choicom86@hanmail.net.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: fuelforlife@naver.com.
authors.forename: Kang-Yo
authors.initials: KY
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: ycfkdk89@naver.com.
authors.forename: Dong Gwang
authors.initials: DG
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: 1989sh@hanmail.net.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Jung
authors.affiliation: The Division of Natural Medical Sciences, College of Health Science, Chosun University, Gwangju 501-759, Republic of Korea. Electronic address: seonh@chosun.ac.kr.
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Oh
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: lee@snu.ac.kr.
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology*; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006710:Homocysteine / Q000633:toxicity*; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000235:genetics
chemical_list: C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D000071717:X-Box Binding Protein 1; D006710:Homocysteine; D051742:Transcription Factor CHOP; D012694:Serine; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D012696:Glycine Hydroxymethyltransferase; D003541:Cystathionine beta-Synthase; D005998:Glycine
keywords: Endoplasmic reticulum stress; Endothelial dysfunction; Glycine; Homocysteine; l-Serine