CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells

Elevated plasma homocysteine levels can induce vascular endothelial dysfunction; however, the mechanisms regulating homocysteine metabolism in impaired endothelial cells are currently unclear. In this study, we deleted the essential mitoribosomal gene CR6 interacting factor 1 (CRIF1) in human umbili...

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Autores principales:	Ikjun Lee, Shuyu Piao, Seonhee Kim, Harsha Nagar, Su-Jeong Choi, Byeong Hwa Jeon, Sang-Ha Oh, Kaikobad Irani, Cuk-Seong Kim
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	CR6 interacting factor 1 dihydrofolate reductase homocysteine folic acid Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/b96589ec9a694c9880c8d88e7f70f8a6
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spelling	oai:doaj.org-article:b96589ec9a694c9880c8d88e7f70f8a62021-11-25T16:25:17ZCRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells10.3390/antiox101116452076-3921https://doaj.org/article/b96589ec9a694c9880c8d88e7f70f8a62021-10-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1645https://doaj.org/toc/2076-3921Elevated plasma homocysteine levels can induce vascular endothelial dysfunction; however, the mechanisms regulating homocysteine metabolism in impaired endothelial cells are currently unclear. In this study, we deleted the essential mitoribosomal gene CR6 interacting factor 1 (CRIF1) in human umbilical vein endothelial cells (HUVECs) and mice to induce endothelial cell dysfunction; then, we monitored homocysteine accumulation. We found that CRIF1 downregulation caused significant increases in intracellular and plasma concentrations of homocysteine, which were associated with decreased levels of folate cycle intermediates such as 5-methyltetrahydrofolate (MTHF) and tetrahydrofolate (THF). Moreover, dihydrofolate reductase (DHFR), a key enzyme in folate-mediated metabolism, exhibited impaired activity and decreased protein expression in CRIF1 knockdown endothelial cells. Supplementation with folic acid did not restore DHFR expression levels or MTHF and homocysteine concentrations in endothelial cells with a CRIF1 deletion or DHFR knockdown. However, the overexpression of DHFR in CRIF1 knockdown endothelial cells resulted in decreased accumulation of homocysteine. Taken together, our findings suggest that CRIF1-deleted endothelial cells accumulated more homocysteine, compared with control cells; this was primarily mediated by the disruption of DHFR expression.Ikjun LeeShuyu PiaoSeonhee KimHarsha NagarSu-Jeong ChoiByeong Hwa JeonSang-Ha OhKaikobad IraniCuk-Seong KimMDPI AGarticleCR6 interacting factor 1dihydrofolate reductasehomocysteinefolic acidTherapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1645, p 1645 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CR6 interacting factor 1 dihydrofolate reductase homocysteine folic acid Therapeutics. Pharmacology RM1-950
spellingShingle	CR6 interacting factor 1 dihydrofolate reductase homocysteine folic acid Therapeutics. Pharmacology RM1-950 Ikjun Lee Shuyu Piao Seonhee Kim Harsha Nagar Su-Jeong Choi Byeong Hwa Jeon Sang-Ha Oh Kaikobad Irani Cuk-Seong Kim CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells
description	Elevated plasma homocysteine levels can induce vascular endothelial dysfunction; however, the mechanisms regulating homocysteine metabolism in impaired endothelial cells are currently unclear. In this study, we deleted the essential mitoribosomal gene CR6 interacting factor 1 (CRIF1) in human umbilical vein endothelial cells (HUVECs) and mice to induce endothelial cell dysfunction; then, we monitored homocysteine accumulation. We found that CRIF1 downregulation caused significant increases in intracellular and plasma concentrations of homocysteine, which were associated with decreased levels of folate cycle intermediates such as 5-methyltetrahydrofolate (MTHF) and tetrahydrofolate (THF). Moreover, dihydrofolate reductase (DHFR), a key enzyme in folate-mediated metabolism, exhibited impaired activity and decreased protein expression in CRIF1 knockdown endothelial cells. Supplementation with folic acid did not restore DHFR expression levels or MTHF and homocysteine concentrations in endothelial cells with a CRIF1 deletion or DHFR knockdown. However, the overexpression of DHFR in CRIF1 knockdown endothelial cells resulted in decreased accumulation of homocysteine. Taken together, our findings suggest that CRIF1-deleted endothelial cells accumulated more homocysteine, compared with control cells; this was primarily mediated by the disruption of DHFR expression.
format	article
author	Ikjun Lee Shuyu Piao Seonhee Kim Harsha Nagar Su-Jeong Choi Byeong Hwa Jeon Sang-Ha Oh Kaikobad Irani Cuk-Seong Kim
author_facet	Ikjun Lee Shuyu Piao Seonhee Kim Harsha Nagar Su-Jeong Choi Byeong Hwa Jeon Sang-Ha Oh Kaikobad Irani Cuk-Seong Kim
author_sort	Ikjun Lee
title	CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells
title_short	CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells
title_full	CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells
title_fullStr	CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells
title_full_unstemmed	CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells
title_sort	crif1 deficiency increased homocysteine production by disrupting dihydrofolate reductase expression in vascular endothelial cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b96589ec9a694c9880c8d88e7f70f8a6
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CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells

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