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

Ikjun Lee; Shuyu Piao; Seonhee Kim; Harsha Nagar; Su-Jeong Choi; Byeong Hwa Jeon; Sang-Ha Oh; Kaikobad Irani; Cuk-Seong Kim

doi:10.3390/antiox10111645

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

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

Ikjun Lee, Shuyu Piao, Seonhee Kim, Harsha Nagar, Su-Jeong Choi, Byeong Hwa Jeon, Sang-Ha Oh, Kaikobad Irani and Cuk-Seong Kim

Antioxidants, Vol.10(11), p.1645

11/01/2021

DOI: 10.3390/antiox10111645

PMCID: PMC8614757

PMID: 34829516

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Abstract

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.

Biochemistry & Molecular Biology

Chemistry, Medicinal

Food Science & Technology

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Science & Technology

Details

Title: Subtitle: CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells
Creators: Ikjun Lee - Chungnam National University
Shuyu Piao - Chungnam National University
Seonhee Kim - Chungnam National University
Harsha Nagar - Chungnam National University
Su-Jeong Choi - Chungnam Natl Univ, Coll Med, Dept Physiol & Med Sci, Daejeon 301747, South Korea
Byeong Hwa Jeon - Chungnam National University
Sang-Ha Oh - Chungnam National University
Kaikobad Irani - Roy J. and Lucille A. Carver College of Medicine
Cuk-Seong Kim - Chungnam National University
Resource Type: Journal article
Publication Details: Antioxidants, Vol.10(11), p.1645
DOI: 10.3390/antiox10111645
PMID: 34829516
PMCID: PMC8614757
NLM abbreviation: Antioxidants (Basel)
ISSN: 2076-3921
eISSN: 2076-3921
Publisher: Mdpi
Number of pages: 15
Grant note: NRF-2014R1A6A1029617; NRF-2019R1I1A3A01059497 / Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education
Language: English
Date published: 11/01/2021
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984313079502771

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