PMID- 38531978
OWN - NLM
STAT- MEDLINE
DCOM- 20240328
LR  - 20240329
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 14
IP  - 1
DP  - 2024 Mar 26
TI  - Homocysteine metabolites inhibit autophagy by upregulating miR-21-5p, miR-155-5p, 
      miR-216-5p, and miR-320c-3p in human vascular endothelial cells.
PG  - 7151
LID - 10.1038/s41598-024-57750-3 [doi]
LID - 7151
AB  - Nutritional and genetic deficiencies in homocysteine (Hcy) metabolism lead to 
      hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of 
      atherosclerosis, which is a major cause of cardiovascular disease (CVD). Impaired 
      autophagy causes the accumulation of damaged proteins and organelles and is 
      associated with CVD. Biochemically, HHcy is characterized by elevated levels of 
      Hcy and its metabolites, Hcy-thiolactone and N-Hcy-protein. However, whether 
      these metabolites can dysregulate mTOR signaling and autophagy in endothelial 
      cells is not known. Here, we examined the influence of Hcy-thiolactone, 
      N-Hcy-protein, and Hcy on autophagy human umbilical vein endothelial cells. We 
      found that treatments with Hcy-thiolactone, N-Hcy-protein, or Hcy significantly 
      downregulated beclin 1 (BECN1), autophagy-related 5 (ATG5), autophagy-related 7 
      (ATG7), and microtubule-associated protein 1 light chain 3 (LC3) mRNA and protein 
      levels. We also found that these changes were mediated by upregulation by 
      Hcy-thiolactone, N-Hcy-protein, and Hcy of autophagy-targeting microRNA (miR): 
      miR-21, miR-155, miR-216, and miR-320c. The effects of these metabolites on 
      levels of miR targeting autophagy as well as on the levels of BECN1, ATG5, ATG7, 
      and LC3 mRNA and protein were abrogated by treatments with inhibitors of miR-21, 
      miR-155, miR-216, and mir320c. Taken together, our findings show that Hcy 
      metabolites can upregulate miR-21, miR-155, miR-216, and mir320c, which then 
      downregulate autophagy in human endothelial cells, important for vascular 
      homeostasis.
CI  - (c) 2024. The Author(s).
FAU - Witucki, Lukasz
AU  - Witucki L
AD  - Department of Biochemistry and Biotechnology, Poznan University of Life Sciences, 
      60-632, Poznan, Poland.
FAU - Jakubowski, Hieronim
AU  - Jakubowski H
AD  - Department of Biochemistry and Biotechnology, Poznan University of Life Sciences, 
      60-632, Poznan, Poland. jakubows@rutgers.edu.
AD  - Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey 
      Medical School, International Center for Public Health, Rutgers University, 225 
      Warren Street, Newark, NJ, 07103, USA. jakubows@rutgers.edu.
LA  - eng
GR  - 2016/23/N/NZ3/01216/National Science Center, Poland/
GR  - 2016/23/N/NZ3/01216/National Science Center, Poland/
GR  - 2019/33/B/NZ4/01760/Narodowe Centrum Nauki/
GR  - 17GRNT32910002/American Heart Association/
PT  - Journal Article
DEP - 20240326
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (MicroRNAs)
RN  - D5H88XF24X (homocysteine thiolactone)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 0 (Beclin-1)
RN  - 0 (RNA, Messenger)
RN  - 0 (MIRN155 microRNA, human)
RN  - 0 (MIRN21 microRNA, human)
RN  - 0 (MIRN216 microRNA, human)
SB  - IM
MH  - Humans
MH  - *MicroRNAs/genetics
MH  - Human Umbilical Vein Endothelial Cells/metabolism
MH  - Homocysteine/metabolism/*analogs & derivatives
MH  - *Cardiovascular Diseases/metabolism
MH  - Beclin-1/metabolism
MH  - Autophagy
MH  - RNA, Messenger/metabolism
PMC - PMC10966103
OTO - NOTNLM
OT  - Autophagy
OT  - Endothelial dysfunction
OT  - HUVEC
OT  - Homocysteine metabolites
OT  - microRNA
COIS- The authors declare no competing interests.
EDAT- 2024/03/27 06:43
MHDA- 2024/03/28 06:45
PMCR- 2024/03/26
CRDT- 2024/03/27 00:24
PHST- 2023/07/24 00:00 [received]
PHST- 2024/03/21 00:00 [accepted]
PHST- 2024/03/28 06:45 [medline]
PHST- 2024/03/27 06:43 [pubmed]
PHST- 2024/03/27 00:24 [entrez]
PHST- 2024/03/26 00:00 [pmc-release]
AID - 10.1038/s41598-024-57750-3 [pii]
AID - 57750 [pii]
AID - 10.1038/s41598-024-57750-3 [doi]
PST - epublish
SO  - Sci Rep. 2024 Mar 26;14(1):7151. doi: 10.1038/s41598-024-57750-3.