PMID- 36990164
OWN - NLM
STAT- MEDLINE
DCOM- 20230609
LR  - 20230613
IS  - 1879-1220 (Electronic)
IS  - 0960-0760 (Linking)
VI  - 231
DP  - 2023 Jul
TI  - The inhibitory effect of vitamin D on myocardial homocysteine levels involves 
      activation of Nrf2-mediated methionine synthase.
PG  - 106303
LID - S0960-0760(23)00058-4 [pii]
LID - 10.1016/j.jsbmb.2023.106303 [doi]
AB  - BACKGROUND: Homocysteine (Hcy) is a synthetic amino acid containing sulfhydryl 
      group, which is an intermediate product of the deep metabolic pathway of 
      methionine and cysteine. The abnormal increase in fasting plasma total Hcy 
      concentration caused by various factors is called hyperhomocysteine (HHcy). HHcy 
      is closely relevant to the occurrence and progression of diverse cardiovascular 
      and cerebrovascular diseases, such as coronary heart disease, hypertension and 
      diabetes, etc. Vitamin D/vitamin D receptor (VDR) pathway is pointed out that 
      prevent cardiovascular disease by reducing serum homocysteine levels. Our 
      research is designed to explore the potential mechanism of vitamin D in the 
      prevention and treatment of HHcy. METHODS AND RESULTS: The Hcy and 25(OH)D(3) 
      levels in mouse myocardial tissue, serum or myocardial cells were detected using 
      ELISA kits. The expression levels of VDR, Nrf2 and methionine synthase (MTR) were 
      observed using Western blotting, immunohistochemistry and real time polymerase 
      chain reaction (PCR). General information of the mice, including diet, water 
      intake and body weight, was recorded. Vitamin D up-regulated the mRNA and protein 
      expression of Nrf2 and MTR in mouse myocardial tissue and cells. CHIP assay 
      determined that the combination of Nrf2 binding to the S1 site of the MTR 
      promoter in cardiomyocytes using traditional PCR and real time PCR. Dual 
      Luciferase Assay was applied to detect the transcriptional control of Nrf2 on 
      MTR. The up-regulation effect of Nrf2 on MTR was verified by Nrf2 knockout and 
      overexpression in cardiomyocytes. The role of Nrf2 in vitamin D inhibition of Hcy 
      was revealed using Nrf2-knockdown HL-1 cells and Nrf2 heterozygous mice. Western 
      blotting, real time PCR, IHC staining and ELISA showed that Nrf2 deficiency could 
      restrain the increase in MTR expression and the decrease in Hcy level induced by 
      vitamin D. The transcriptional activities of Nrf2/MTR were activated by vitamin 
      D/VDR with a decrease in Hcy. CONCLUSION: Vitamin D/VDR upregulates MTR in an 
      Nrf2-dependent manner, thereby reducing the risk of HHcy.
CI  - Copyright (c) 2023 Elsevier Ltd. All rights reserved.
FAU - Sun, Xiaoqi
AU  - Sun X
AD  - Department of Clinical Nutrition, Shengjing Hospital of China Medical University, 
      Shenyang 110004, China.
FAU - Liu, Ning
AU  - Liu N
AD  - Department of Clinical Nutrition, Shengjing Hospital of China Medical University, 
      Shenyang 110004, China.
FAU - Sun, Can
AU  - Sun C
AD  - Department of Clinical Nutrition, Shengjing Hospital of China Medical University, 
      Shenyang 110004, China.
FAU - Xu, Yingxi
AU  - Xu Y
AD  - Department of Clinical Nutrition, Shengjing Hospital of China Medical University, 
      Shenyang 110004, China.
FAU - Ding, Ding
AU  - Ding D
AD  - Department of Clinical Nutrition, Shengjing Hospital of China Medical University, 
      Shenyang 110004, China.
FAU - Kong, Juan
AU  - Kong J
AD  - Department of Clinical Nutrition, Shengjing Hospital of China Medical University, 
      Shenyang 110004, China. Electronic address: kongj@cmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230328
PL  - England
TA  - J Steroid Biochem Mol Biol
JT  - The Journal of steroid biochemistry and molecular biology
JID - 9015483
RN  - 1406-16-2 (Vitamin D)
RN  - 0 (NF-E2-Related Factor 2)
RN  - EC 2.1.1.13 (5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase)
RN  - 0 (Vitamins)
RN  - AE28F7PNPL (Methionine)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Vitamin D/pharmacology
MH  - *NF-E2-Related Factor 2/genetics
MH  - 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/genetics
MH  - Vitamins
MH  - Methionine
OTO - NOTNLM
OT  - Homocysteine
OT  - Methionine synthase
OT  - Nrf2
OT  - Vitamin D
COIS- Conflict of interest All authors state that no conflict of interest.
EDAT- 2023/03/30 06:00
MHDA- 2023/06/09 06:42
CRDT- 2023/03/29 19:30
PHST- 2022/09/13 00:00 [received]
PHST- 2023/02/18 00:00 [revised]
PHST- 2023/03/26 00:00 [accepted]
PHST- 2023/06/09 06:42 [medline]
PHST- 2023/03/30 06:00 [pubmed]
PHST- 2023/03/29 19:30 [entrez]
AID - S0960-0760(23)00058-4 [pii]
AID - 10.1016/j.jsbmb.2023.106303 [doi]
PST - ppublish
SO  - J Steroid Biochem Mol Biol. 2023 Jul;231:106303. doi: 
      10.1016/j.jsbmb.2023.106303. Epub 2023 Mar 28.